REVIEW The Journal of Clinical Investigation

The extracellular matrix in myocardial injury, repair, and remodeling

Nikolaos G. Frangogiannis Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, New York, New York, USA.

The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct . Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration.

Introduction defines major bundles, and the encases the entire The mammalian myocardium comprises cardiomyocytes and (5, 6). In all mammalian species studied to date, large populations of interstitial noncardiomyocytes (1) enmeshed type I is the major structural component of the cardiac within an intricate network of extracellular matrix (ECM) proteins. interstitium, accounting for approximately 85% to 90% of the col- In health, the cardiac ECM does not simply serve as a mechanical lagenous matrix (7), and is predominantly localized in the epimy- scaffold, but may also transduce signals that are important for cell sium and . In contrast, type III collagen represents 5% survival and function. Most cardiac pathologic conditions are asso- to 11% of total myocardial collagen and is more prominent in the ciated with expansion of the cardiac interstitial matrix and with (7–9). In addition to , the cardiac ECM also marked alterations in its composition (2, 3); these changes perturb contains fibronectin, glycosaminoglycans, and proteoglycans, and cardiac systolic and diastolic function. In myocardial infarction, it serves as a reservoir for growth factors and proteases, which are sudden death of up to a billion cardiomyocytes overwhelms the stored in the normal matrix and can be activated following injury. extremely limited regenerative capacity of the adult mammalian Although the role of the matrix network in providing structural heart. As a result, the infarcted ventricle heals through activation support, preserving ventricular geometry, and facilitating force of a superbly orchestrated cellular response that clears the wound transmission is intuitive, the collagen-based cardiac matrix also of dead cells and matrix debris, ultimately leading to formation of transduces key signals necessary for survival and function of both a collagen-based scar (4). In conditions associated with pressure cardiomyocytes and noncardiomyocytes. The molecular pathways or volume overload, dynamic alterations in the ECM network responsible for the interactions between matrix proteins and the may affect cardiomyocyte survival and may regulate the response cellular elements in normal hearts remain poorly understood. of interstitial cells to mechanical stress. Metabolic diseases are also associated with profound alterations in the composition of Alterations of the ECM network following the cardiac ECM that contribute to the pathogenesis of diastolic myocardial infarction dysfunction and may suppress the myocardial reparative reserve. Repair of the infarcted myocardium can be divided into three dis- Despite increased recognition of its role in mediating cell bio- tinct but overlapping phases: the inflammatory phase, the prolifer- logical responses, the contribution of the ECM in cardiac patho- ative phase, and the maturation phase (10). In all three phases of physiology remains underappreciated. This Review discusses the infarct healing, the dynamic changes in the composition of the ECM dynamic alterations of the ECM following cardiac injury and their play a critical role in regulation of the cellular responses that medi- contribution to cardiac remodeling and function. ate cardiac repair (11). During the inflammatory phase, early deg- radation of matrix proteins generates bioactive fragments (termed The ECM network in the normal mammalian heart matrikines) that may contribute to activation of inflammatory and The myocardial matrix network comprises primarily fibrillary col- reparative cascades (Figure 1). Moreover, formation of a provi- lagen that is organized on three interconnected levels: the endo- sional matrix network derived from extravasated plasma proteins mysium surrounds individual cardiomyocytes, the perimysium serves as a highly plastic conduit for infiltrating inflammatory cells. Removal of dead cells and matrix debris by professional phagocytes induces release of antiinflammatory mediators, marking the tran- Conflict of interest: The author has declared that no conflict of interest exists. Reference information: J Clin Invest. 2017;127(5):1600–1612. sition to the proliferative phase of cardiac repair. At this stage, the https://doi.org/10.1172/JCI87491. ECM is enriched through induction and deposition of matricellular

1600 jci.org Volume 127 Number 5 May 2017 The Journal of Clinical Investigation REVIEW

Figure 1. The ECM during the inflammatory phase of cardiac repair. (A) Cardiomyocyte necrosis is associated with induction and activation of proteases in the infarcted region. Activated proteases cause fragmentation of the native ECM, resulting in release of matrikines, bioactive peptides that activate an inflammatory macrophage phenotype and may also modulate responses of fibroblasts and vascular endothelial cells. The effects of MMPs in the ischemic and infarcted myocardium are not limited to the ECM. MMPs may modulate inflammatory and reparative responses by processing cytokines and chemok- ines. They may also inhibit chemokine actions by degrading glycosaminoglycan-binding sites and mediate dysfunction by targeting intracellular proteins. Increased vessel permeability in the infarcted region results in extravasation of plasma proteins, such as fibrinogen and fibronectin. Accumulation of these proteins in the infarcted region forms a provisional matrix that serves as a scaffold for infiltrating leukocytes. Fibrin and fibronectin modulate the phenotype of immune and reparative cells through integrin-mediated actions. (B) Fibrinogen/fibrin staining using a peroxidase-based technique (black) illustrates the formation of the provisional fibrin-based matrix network (indicated by arrows) in the infarcted canine myocardium (one hour ischemia followed by seven days reperfusion). Counterstained with eosin. Scale bar: 50 μm. Reproduced with permission from the FASEB Journal (155).

proteins, defined as extracellular macromolecules that do not serve ECM during the inflammatory phase of a primary structural role, but modulate cellular phenotype, activate cardiac repair proteases and growth factors, and transduce signaling cascades (12, Activation of matrix metalloproteinases. Myocardial ischemia caus- 13). Activated myofibroblasts are the dominant cells during the pro- es rapid activation of latent matrix metalloproteinases (MMPs) liferative phase of cardiac repair and deposit large amounts of struc- and subsequent generation of matrix fragments (14, 15). MMP tural ECM proteins. Finally, during the maturation phase, crosslink- activation is detected in the cardiac interstitium as early as ten ing of the ECM, fibroblast quiescence, and vascular maturation lead minutes after coronary occlusion (16), before any evidence of irre- to formation of a stable collagen-based scar. versible cardiomyocyte injury, and may be driven by ischemia-

jci.org Volume 127 Number 5 May 2017 1601 REVIEW The Journal of Clinical Investigation mediated ROS generation (17). Cardiomyocyte necrosis accentu- dynamic fibrin-based matrix network (39, 49). The role of the pro- ates the matrix-degrading response. Large amounts of MMPs are visional matrix in regulating cardiac repair remains poorly under- synthesized de novo by ischemic cardiomyocytes, fibroblasts, endo- stood; current concepts are predominantly based on extrapolation thelial cells, and inflammatory leukocytes that infiltrate the infarct of findings from studies that investigate reparative responses in (18). Both collagenases (e.g., MMP1) and gelatinases (MMP2 and other systems. In addition to its hemostatic role, the provisional MMP9) are upregulated in the infarcted myocardium (19). matrix may serve as a scaffold for migrating inflammatory cells It should be emphasized that the actions of MMPs are not lim- and support proliferating endothelial cells and fibroblasts (50). ited to effects on the ECM. MMPs regulate inflammatory responses Components of the provisional matrix interact with migrating through proteolytic processing of cytokines, chemokines, and growth cells through cell surface integrins (51) and may also transduce factors (20–24) or by degrading glycosaminoglycan binding sites, signaling cascades that modulate immune cell phenotype and thus interfering with a molecular step that is critical for chemokine gene expression (52). In vitro, fibrinogen stimulates macrophage- immobilization on the endothelial cell surface and subsequent inter- derived chemokine secretion through TLR4 activation (53). action with leukocytes (25). MMPs also have intracellular targets, In a mouse model of reperfused myocardial infarction, degrading cardiomyocyte proteins, such as , α-actinin, and fibrin-mediated interactions contributed to early injury by accen- (26–28). The relative significance of the matrix-independent tuating the inflammatory response (54). Treatment with a nat- actions of MMPs in the pathogenesis of ischemic dysfunction and urally occurring peptide that competes with the fibrin fragment postinfarction remodeling remains unknown. N-terminal disulfide knot-II (an analog of the fibrin E1 fragment) Generation of matrikines. In injured and remodeling tissues, for binding to vascular endothelial cadherin reduced infarct size, protease-mediated fragmentation of matrix proteins results in attenuating leukocyte infiltration in the ischemic myocardium generation of matrikines (29–32). Elastin fragments and colla- in both rodent and large animal models (54, 55). Unfortunately, gen-derived peptides are the best-studied matrikines and have the effects of the peptide in a small clinical trial were much less been implicated in activation of immune cells and fibroblasts impressive. Peptide administration in patients with ST-elevation (29, 33). The collagen-derived tripeptide proline-glycine-proline myocardial infarction (STEMI) did not affect the size of the infarct (PGP) and its acetylated form have been demonstrated as acting assessed through magnetic resonance imaging and did not reduce as neutrophil chemoattractants in models of pulmonary inflam- serum I levels (56). mation, signaling through activation of the chemokine receptor The provisional matrix may also play an important role in the CXCR2 (34). PGP generation requires activation of a multistep transition to the proliferative phase of cardiac repair by serving as cascade that involves MMP8, MMP9, and prolyl endopeptidase a reservoir for cytokines and growth factors. The heparin-binding (35). Proteolytic processing of laminins by MMP2 and MMP14 has domain of fibrin binds to a wide range of growth factors, includ- also been demonstrated as yielding fragments with potent neutro- ing members of the PDGF, FGF, VEGF, and TGF families (57), that phil chemoattractant properties (36). may activate reparative fibroblasts and vascular cells. Although the rapid activation of MMPs in the infarct is asso- ciated with matrix fragmentation, the role of these fragments as ECM during the proliferative phase of bioactive proinflammatory matrikines has not been documented. infarct healing In experimental models, release of type I collagen fragments in Dynamic changes in the composition of the ECM may contribute the serum has been documented within 30 minutes after coronary to the reparative cellular responses during the proliferative phase occlusion (37). Fragmentation of components of the basement of cardiac repair (Figure 2). Clearance of matrix fragments by membrane, such as collagen IV, and of noncollagenous matrix phagocytes may activate antiinflammatory signals, suppressing constituents has also been demonstrated in the infarcted myocar- recruitment of proinflammatory leukocytes. Lysis of the plas- dium (38–41). Low–molecular weight hyaluronan fragments exert ma-derived provisional matrix is followed by organization of a potent proinflammatory actions in the infarcted region; impaired cell-derived matrix network, comprising cellular fibronectin, hyal- clearance of these fragments has been shown to prolong and uronan, proteoglycans, and a wide range of matricellular macro- accentuate proinflammatory signaling in leukocytes and vascu- molecules (39) that transduce growth factor signals to reparative lar cells (42, 43). Matrix fragments may also modulate fibroblast cells (58). The dynamic alterations of the ECM during the prolifer- and vascular cell phenotype (44). Endostatin, a 20-kDa fragment ative phase provide essential signals for conversion of fibroblasts of collagen XVIII, exerts potent angiostatic actions (45) and stim- into myofibroblasts and may activate angiogenic pathways nec- ulates fibroblast proliferation (46). MMP9-mediated cleavage of essary for neovessel formation, thus supplying the metabolically collagen IV also generates fragments with angiostatic properties, active wound with oxygen and nutrients (11). such as tumstatin (47). The role of endogenous matrix fragments Fibrin network clearance and cell-derived provisional matrix for- in regulation of fibrogenic and angiogenic responses following mation. In healing wounds, the plasma-derived ECM is cleared myocardial infarction remains poorly understood. through extracellular proteolysis by fibrinolytic enzymes (59) and The plasma-derived provisional matrix regulates the inflammato- through endocytosis by CCR2+ macrophages (60). In the healing ry response. Degradation of the original cardiac matrix network in infarct, clearance of the fibrin-based provisional matrix by the the infarcted myocardium is accompanied by formation of a provi- plasminogen/plasmin system is an important part of the reparative sional matrix (39). Rapid induction of VEGF in the infarcted heart response. Mice lacking plasminogen exhibited markedly atten- increases vascular permeability (48), leading to extravasation of uated recruitment of inflammatory leukocytes in the infarct and plasma fibrinogen and fibronectin and generating a complex and impaired granulation tissue formation (61). Lysis of the fibrin-based

1602 jci.org Volume 127 Number 5 May 2017 The Journal of Clinical Investigation REVIEW

been implicated in conver- sion. In vitro, pericellular hyaluronan was required to maintain a myofibroblast phe- notype in TGF-β–stimulated cells (67). In vivo, loss of CD44, the main receptor for haluronan, impaired collagen synthesis in infarct fibroblasts (40). Versican loss in dermal fibroblasts attenuated myofibro- blast conversion (68). Although versican is upregulated in healing myocardial infarcts (69), its in vivo role in transdifferentiation of injury-site cardiac myofibroblasts has not been directly documented. Induction of matricellular proteins. During the proliferative phase of infarct healing, the cardiac ECM is enriched through the deposition of a wide range of structurally diverse matricellular proteins that do not serve a direct structural role, but act contextually by regulating cytokine and growth factor responses and modulating Figure 2. The role of the cell-derived provisional matrix in cardiac repair. (A) During the proliferative phase of cardiac repair, fibroblasts and macrophages contribute to the formation of a cell-derived cell phenotype and function (70, 71). The provisional matrix, enriched with a wide range of matricellular macromolecules that do not serve a family includes the thrombospondins TSP- primary structural role, but modulate cellular phenotype and function. Specialized matrix proteins 1, -2, and -4, tenascin-C and -X, secreted (such as ED-A domain fibronectin) and matricellular proteins, such as TSPs, tenascin-C (TNC), osteo- protein, acidic and cysteine-rich (SPARC), pontin (OPN), SPARC, periostin, osteoglycin, and members of the CCN family, bind to the matrix and osteopontin, periostin, and members of modulate growth factor and protease activity. Specific matricellular proteins have been reported as regulating inflammation, participating in fibrogenic and angiogenic responses, modulating cardio- the CCN family (72). Several other pro- myocyte survival, and contributing to assembly of the structural matrix. (B) Matricellular proteins teins (including members of the galectin may be critical in spatial and temporal regulation of growth factor signaling. Immunohistochemical and syndecan family, fibulins, osteoglycin, staining using a peroxidase-based technique (black) shows the strikingly selective localization of the and other small leucine-rich proteoglycans) prototypical matricellular protein TSP1 (arrows), a critical activator of TGF-β, in the border zone of a have been found to exert matricellular healing canine myocardial infarction (one hour ischemia followed by seven days reperfusion). Spa- tially and temporally restricted induction of matricellular proteins regulates growth factor signaling, actions as part of their broader spectrum of preventing expansion of profibrotic responses beyond the infarcted area, despite possible diffusion functional properties. Most members of the of the soluble mediators in viable segments. Counterstained with eosin. Reproduced with permission matricellular family show low expression in from Circulation (75). Scale bar: 50 μm. GAGs, glycosaminoglycosans. the normal myocardium, but are markedly upregulated following myocardial injury. In healing infarctions, angiotensin and growth matrix is followed by secretion of cellular fibronectin by fibroblasts factors stimulate de novo synthesis and secretion of matricellular and macrophages (62, 63) and by deposition of hyaluronan and proteins in fibroblasts or immune or vascular cells (39, 73, 74). versican, forming a network of cell-derived provisional matrix that Once secreted into the interstitium, matricellular macromolecules is later enriched with a wide range of matricellular macromolecules bind to the structural matrix and transduce signaling cascades (12). During the proliferative phase of healing, the highly dynamic through ligation of cell surface receptors or contribute to activa- matrix becomes a regulatory center that transduces essential sig- tion of cytokines, growth factors, and proteases in the pericellular nals to activate reparative fibroblasts and vascular cells. space. An overview of the pattern of regulation, function, targets, Components of the provisional matrix regulate fibroblast activa- and mechanisms of action of the matricellular proteins discussed tion. Repair of the infarcted heart is dependent on recruiting and below is given in Table 1. activating resident fibroblast populations (64) to acquire a myo- Several prototypical members of the matricellular family are fibroblast phenotype that expresses contractile proteins such as markedly upregulated following myocardial infarction and pro- α- (α-SMA) and secretes large amounts of col- tect the myocardium from adverse remodeling (75–78). Localized lagens. Myofibroblast transdifferentiation requires cooperation induction of TSP-1 in the infarct border zone may form a barrier between soluble growth factors, such as TGF-β1, and components that prevents expansion of inflammation in viable myocardial areas of the provisional matrix. In vitro, the ED-A domain splice variant through local activation of antiinflammatory signals (75). Osteopon- of fibronectin is critical for TGF-β1–mediated α-SMA upregulation tin may protect from left ventricular dilation by promoting matrix (65). In vivo, ED-A fibronectin loss attenuates myofibroblast trans- deposition in the infarcted region (79). SPARC has been shown to differentiation in healing myocardial infarction (66). The specific protect from cardiac rupture and postinfarction heart failure by con- interactions between the ED-A segment and the TGF-β–signaling tributing to collagen maturation through activation of growth factor cascade remain unknown. Hyaluronan and versican have also signaling (80). Periostin serves as a crucial regulator of fibroblast

jci.org Volume 127 Number 5 May 2017 1603 REVIEW The Journal of Clinical Investigation recruitment and activity (81) and prevents cardiac rupture (81, 82), environmental cues, interstitial cells exhibit phenotypic changes promoting formation of an organized collagen-based scar. (84–86), leading to transitions from inflammatory to reparative Although each matricellular protein has a unique function- phenotypes (87). Through their transient induction and incorpora- al profile, several unifying themes have emerged regarding their tion into the matrix, matricellular proteins may play a critical role in actions in the infarcted heart. First, the strikingly selective local- regulating cell differentiation, contributing to the cellular plasticity ization of prototypical members of the family in the infarct border observed in healing tissues through direct actions and via modula- zone and their regulatory effects on the activity of soluble medi- tion of growth factor–mediated pathways. ators highlight their role in spatial regulation of cellular respons- es. Secreted growth factors and cytokines can diffuse beyond the ECM in the maturation phase of infarct healing infarct zone; the requirement for matricellular proteins in activating Scar maturation is associated with ECM crosslinking in the infarct growth factor–mediated responses may serve to localize inflamma- zone and with a marked reduction in myofibroblast density (88). tory and fibrotic responses within areas of injury. Second, transient Descriptive studies have suggested that apoptosis may be involved expression of matricellular proteins during the proliferative phase in elimination of granulation tissue cells from the infarct (89, 90); of healing ensures temporal regulation of growth factor respons- however, the mechanisms responsible for cell-specific activation es. Clearance of matricellular proteins from the infarcted area of a proapoptotic program in the late phase of infarct healing have may serve as an important STOP signal, preventing uncontrolled not been investigated. Acquisition of a quiescent phenotype may fibrosis following injury. In vitro studies have demonstrated that precede apoptosis of infarct myofibroblasts. Formation of a mature alternatively activated macrophages internalize SPARC through crosslinked matrix and clearance of matricellular proteins may play the scavenger receptor stabilin 1 (83). However, the potential role an important role in regulating fibroblast deactivation in the healing of immune cell subsets in endocytosis and degradation of matri- infarct (91–93). It is tempting to hypothesize that endogenous mech- cellular proteins in vivo has not been tested. Third, repair of the anisms that restrain matricellular actions protect the infarcted heart infarcted myocardium is dependent on a highly dynamic microen- from progressive fibrosis, depriving fibroblasts of the prolonged vironment that promotes cellular plasticity. In response to micro- actions of growth factor–mediated signals. Vascular cells may also

Table 1. Matricellular proteins in myocardial infarction

Matricellular Pattern of regulation Function Possible cellular targets Possible mechanisms of action References protein TSP-1 Transient upregulation and Protects the infarcted heart from Fibroblasts, macrophages, Activates TGF-β 12 deposition in the infarct border adverse remodeling, limiting vascular endothelial cells, T cells, Inhibits MMPs zone during the proliferative phase expansion of inflammation and cardiomyocytes Exerts angiostatic actions of healing extension of fibrosis Exerts antiinflammatory actions Modulates nitric oxide signaling Tenascin-C Transient upregulation in infarcted May contribute to myocardial Fibroblasts, cardiomyocytes, Exerts proinflammatory actions 145, 156, 157 area, border zone, and remodeling regeneration in fish and amphibians macrophages, vascular cells Triggers fibrogenic actions though myocardium Promotes fibrosis and adverse accentuation of growth factor signaling remodeling in mammals Promotes angiogenic effects SPARC Abundant, but transient Protects from cardiac rupture Fibroblasts, macrophages, vascular Regulates matrix assembly and 80, 158 upregulation in infarcted May promote systolic dysfunction cells metabolism myocardium, predominantly during the early postischemic phase Accentuates growth factor signaling, localized in macrophages and promoting fibroblast activation and myofibroblasts angiogenesis OPN Markedly and transiently Protects from adverse remodeling Fibroblasts, macrophages, T cells, Regulates matrix assembly 79 upregulated following infarction, vascular cells, cardiomyocytes Activates growth factor signaling, primarily localized in macrophages promoting fibroblast activation and angiogenesis Periostin Marked, but transient upregulation Protects from cardiac rupture, Fibroblasts Regulates matrix assembly 81, 82 in activated myofibroblasts in while promoting late fibrosis in Activates a fibrogenic program the infarct, border zone, and remodeling segments remodeling area CCN2 Marked, but transient upregulation Cardiomyocyte-specific CCN2 Cardiomyocytes, fibroblasts, Activates prosurvival pathways in 159, 160 in infarcted hearts through activation overexpression studies suggested macrophages cardiomyocytes of TGF-β and angiotensin II that CCN2 reduces infarct size Attenuates inflammation following ischemia/reperfusion and attenuates adverse remodeling in nonreperfused infarction Osteoglycin Marked upregulation in infarcted Protects from cardiac rupture and Fibroblasts Regulates maturation of collagen fibers 161 myocardium, associated with prevents adverse remodeling collagen deposition

1604 jci.org Volume 127 Number 5 May 2017 The Journal of Clinical Investigation REVIEW

iology of postinfarction remodeling. Pressure and volume overload have distinct effects on the cardiac ECM that may account for their conse- quences on ventricular geometry and function. ECM in the pressure-overloaded myocardi- um. In both experimental models and in human patients, cardiac pressure overload causes early hypertrophic remodeling and diastolic dys- function, followed by decompensation, cham- ber dilation, and development of systolic heart failure. Pressure overload is associated with profound and dynamic changes in the com- position of the ECM; these changes regulate geometry and function, not only by affecting the mechanical properties of the ventricle, but also by modulating cellular responses. In ani- mal models, activation of cardiac fibroblasts is one of the earliest effects of pressure overload in the myocardium, ultimately leading to depo- sition of collagenous matrix and expansion of the interstitium (99–101). In human patients, hypertensive heart disease is associated with Figure 3. Matricellular proteins regulate cellular responses in the pressure-overloaded myocar- development of interstitial and periarteriolar dium. In the pressure-overloaded heart, mechanical stress activates neurohumoral pathways fibrosis even in the absence of significant cor- and induces synthesis and release of matricellular macromolecules, including TSP1, -2, and -4, onary atherosclerosis (102). tenascin-C, OPN, SPARC, and periostin. Matricellular proteins have been implicated in regulation Fibrotic changes that develop in the of matrix assembly, in transduction of mechanosensitive signaling, and in the pathogenesis of fibrosis and cardiac hypertrophy, and may also modulate survival of cardiomyocytes under condi- pressure-overloaded myocardium may involve tions of stress. The effects of the matricellular proteins are exerted through direct activation of activation of cardiomyocytes, fibroblasts, cell surface receptors or through modulation of growth factor– and protease-mediated responses. and immune and vascular cells. Mechani- cal stress due to pressure overload activates the renin-angiotensin-aldosterone system respond to the mature ECM environment. During scar maturation, (RAAS), triggering inflammatory signaling and leading to down- infarct microvessels acquire a coat of mural cells through activation stream stimulation of TGF-β cascades. Neurohumoral mediators, of PDGFR-β signaling (88, 94); uncoated vessels regress. ECM pro- cytokines, and growth factors directly stimulate a fibrogenic pro- teins have been implicated in modulation of endothelial-pericyte gram, triggering myofibroblast conversion and stimulating syn- interactions in vitro and in vivo (95, 96), but whether such effects thesis of large amounts of structural matrix proteins (103–106). play a role in maturation of infarct microvessels remains unknown. Stress-induced fibroblast activation in the pressure-overloaded It should be emphasized that in the presence of a large myocardium may also be indirect, at least in part, requiring stim- infarction with significant hemodynamic consequences, via- ulation of fibrogenic cascades in cardiomyocytes and immune ble noninfarcted myocardium also exhibits slowly progres- cells. Mechanical stretch has been suggested as triggering puriner- sive interstitial fibrosis related to the pathophysiologic effects gic signaling in cardiomyocytes, leading to release of fibrogenic of pressure and volume loads. Inflammation and fibrosis are growth factors (107). Moreover, T lymphocytes and macrophages suppressed in the healing infarct, leading to formation of a have been implicated in activation of resident cardiac fibroblasts mature collagen-based scar, but in the viable noninfarcted following pressure overload (108, 109). zone, increased wall stress may locally activate macrophages Even in the absence of cardiomyocyte necrosis, mechanically and fibroblasts, triggering chronic progressive expansion of the activated myofibroblasts and immune cells secrete specialized matrix cardiac interstitial matrix (97, 98). proteins (such as fibronectin) and enrich the interstitial matrix with a wide range of matricellular macromolecules (Figure 3 and refs. 110, ECM in cardiac pressure and volume overload 111). Fibronectin deposition in the pressure-overloaded heart may be Pressure and volume overload are critically implicated in the patho- involved in myofibroblast transdifferentiation and has been impli- genesis of heart failure in a wide variety of cardiac conditions. Left cated as an important mediator in cardiomyocyte hypertrophy (112), ventricular pressure overload is the critical pathophysiologic com- possibly through activation of growth factor signaling. Deposition of panion of the cardiomyopathy induced by systemic hypertension matricellular proteins in the pressure-overloaded heart generates a and aortic stenosis. On the other hand, valvular regurgitant lesions highly dynamic matrix microenvironment and modulates fibrogenic (such as aortic and mitral insufficiency) cause cardiac remodeling and hypertrophic responses. Table 2 provides an overview of the reg- and heart failure by subjecting the heart to volume overload. More- ulation, functional role, and mechanisms of action of the matricellu- over, both pressure and volume loads contribute to the pathophys- lar proteins in the pressure-overloaded myocardium.

jci.org Volume 127 Number 5 May 2017 1605 REVIEW The Journal of Clinical Investigation

ECM in cardiac volume overload. Volume overload is associat- The cardiac ECM in metabolic disease ed with a distinct profile of changes in the composition of the ECM Diabetics exhibit a high incidence of heart failure with preserved that ultimately lead to chamber dilation and contribute to systolic ejection fraction, associated with expansion of the cardiac ECM dysfunction. In contrast to the marked accentuation in collagen network (120). Fibrotic changes in diabetic hearts are, at least deposition triggered by a pressure load, volume overload is asso- in part, independent of coronary artery disease or hypertension ciated with a reduction in interstitial collagen content due to (121), reflecting direct effects of metabolic dysregulation on the increased MMP expression (113–115) and augmented autophag- ECM. Diabetes, obesity, and metabolic dysfunction are associated ic degradation of procollagen in cardiac fibroblasts (116). Phar- with activation of cardiac fibroblasts (122) and are accompanied macologic inhibition studies suggested that MMP activation is by deposition of matricellular macromolecules (123) and progres- directly implicated in dilative remodeling of the volume-over- sive accumulation of fibrillary collagens in the cardiac interstitium loaded ventricle (117), but the mechanisms responsible for the (124, 125). The molecular basis for activation of the so-called dia- distinct cell biological changes and matrix alterations in volume betic fibroblast remains unknown. The role of hyperglycemia in overload remain poorly understood. Bradykinin receptor signal- mediating fibrogenic activation remains poorly defined. Whether ing has been implicated in matrix loss associated with volume stimulation of a fibrogenic program in diabetic fibroblasts requires overload (118), but the links between specific mechanical stim- diabetes-associated activation of fibrogenic signaling in cardiomyo- uli and myocardial cell activation are understudied. The limited cytes, vascular, or immune cells is unclear. Expansion of the cardiac data on the matricellular protein profile in volume-overload- interstitium in diabetes involves activation of several distinct but ed hearts are not accompanied by systematic investigations of overlapping pathways, including neurohumoral mediators (such as the potential role of these proteins. Although marked increas- the RAAS), ROS, inflammatory cytokines and growth factors (such es in synthesis of fibronectin and periostin have been report- as TGF-β), adipokines, and the advanced glycation endproduct ed in experimental volume overload (114, 119), deposition of (AGE)/receptor for AGE (RAGE) axis. Moreover, hyperglycemia these fibrogenic matricellular proteins was not associated with induces matricellular protein synthesis in several cell types (126). increased secretion of structural matrix proteins. Diabetes-associated induction of matricellular proteins, such as

Table 2. Matricellular proteins in the pressure-overloaded myocardium

Matricellular Pattern of regulation in models Function Possible mechanisms of action References protein of pressure overload TSP-1 Transient upregulation and deposition in Activates fibroblasts in the pressure-overloaded Activates TGF-β 111, 162–164 interstitial and perivascular areas in models of heart, promoting a matrix-synthetic phenotype Inhibits MMP activity TAC and systemic hypertension and in a combined model of hyperglycemia/abdominal aortic constriction TSP-2 High expression in myocardium of renin- Protects the angiotensin II–stimulated myocardium Inhibition of MMP synthesis and activity 165, 166 overexpressing hypertensive rats that developed from rupture Activation of prosurvival pathways in heart failure Protects the aging heart from dilation cardiomyocytes High expression in human patients with cardiac hypertrophy TSP-4 Rapid upregulation in the myocardium in response Protects the pressure-overloaded heart from Suppresses expression of ECM proteins in 167–171 to angiotensin II treatment or TAC functional decompensation, systolic dysfunction, fibroblasts and endothelial cells and death Activates mechanosensitive Erk and Akt Downmodulates the fibrotic response in the signaling in cardiomyocytes, increasing pressure-overloaded heart contractility following pressure overload Has been suggested as also acting intracellularly, augmenting ER function and protecting from injury-related ER stress Tenascin-C Deposition in the cardiac interstitium following Accelerates cardiac fibrosis in response to May act in part through activation of integrin- 99, 172–174 pressure overload angiotensin II infusion mediated cytokine secretion in macrophages Upregulation in cardiomyocytes subjected to mechanical strain SPARC Upregulation in models of TAC Mediates fibrosis and promotes diastolic Contributes to postsynthetic procollagen 175, 176 dysfunction in models of TAC processing OPN Upregulation in models of TAC and angiotensin II Mediates fibrosis in models of TAC, angiotensin, Promotes fibroblast proliferation infusion and aldosterone infusion Activates fibroblasts through an miR-21– Increased expression in human hypertensive heart Prohypertrophic effects are less consistently mediated pathway 177–183 disease observed in various models Periostin Upregulated in activated fibroblasts and deposited Promotes hypertrophy and fibrosis Activates cardiac fibroblasts, promoting their 82, 184 in the cardiac interstitium in models of TAC migration and transdifferentiation Regulates collagen fibrillogenesis TAC, transverse aortic constriction

1606 jci.org Volume 127 Number 5 May 2017 The Journal of Clinical Investigation REVIEW

TSP-1, may drive the fate of cardiac interstitial cells toward a fibro- of matricellular macromolecules to modulate growth factor and blast phenotype promoting fibrotic remodeling. cytokine signaling, thus localizing therapeutic effects in the area of interest. Unfortunately, the daunting complexity of the biol- Therapeutic ECM targeting in injured and ogy of matricellular proteins hampers therapeutic implementa- remodeling myocardium tion. Matricellular proteins have multiple functional domains Matrix-based strategies to preserve structure, geometry, and function. and act contextually depending on microenvironmental fac- Because of its importance in preserving structural integrity and tors, such as the local composition of the matrix and the profile function of the heart (127) and its crucial involvement in regula- of cytokine and growth factor expression. Distinct actions of tion of cellular responses in cardiac injury, repair, and remodeling matricellular protein fragments further complicate therapeu- (12), the cardiac ECM provides unique opportunities for therapeu- tic implementation. Identification of the functional domains tic interventions in patients with myocardial infarction and heart responsible for specific protective or detrimental matricellular failure. Several therapeutic approaches with established benefi- actions is needed in order to design peptide-based strategies cial effects in patients with myocardial infarction and heart fail- that simulate these effects (12, 135). ure, such as ACE inhibition, angiotensin type 1 receptor blockade, Targeting the ECM to promote cardiac regeneration. In con- β-adrenergic receptor antagonism, and mechanical unloading, trast with fish and amphibians, adult mammals have very may exert some of their protective actions through modulation of limited capacity for myocardial regeneration (136), which is ECM deposition and metabolism (128). overwhelmed by the massive sudden loss of cardiomyocytes Following myocardial infarction, catastrophic mechanical following infarction. Over the last 15 years, a wide range of cell complications, such as cardiac rupture (129), are associated with therapy approaches has been tested in attempts to regenerate accentuated matrix degradation or perturbed deposition of new the injured human myocardium, with little success (137–139). structural matrix (130). These can be treated through application Although beneficial actions have been reported with several of a patch containing ECM proteins to restore the structural integ- different types of cell therapy, in many cases, protection of the rity of the ventricle (131). In the remodeling heart, approaches to infarcted myocardium was attributed to paracrine effects and to tightly regulating matrix deposition and crosslinking may pro- the modulation of inflammatory and fibrogenic signals rather tect from adverse remodeling and development of heart failure. than to activation of a regenerative program. A large body of experimental evidence suggests that excessive Several lines of evidence suggest that modulation of the ECM accumulation of crosslinked structural matrix proteins increases may be a crucial component of a regenerative response. First, in myocardial stiffness and promotes diastolic dysfunction; in con- vitro, the composition of the ECM has a profound effect in regu- trast, overactive matrix-degrading pathways may promote dila- lation of cell cycle entry in cardiomyocyte progenitors and in neo- tive remodeling, causing systolic dysfunction. In patients with natal cardiac myocytes (140, 141). Compliant matrices contain- myocardial infarction, therapeutic interventions directly target- ing elastin promote dedifferentiation, proliferation, and clonal ing ECM metabolism through MMP inhibition have produced expansion of rat and mouse neonatal cardiomyocytes (140). Sec- mixed results. Administration of a selective oral MMP inhibitor ond, in fish and amphibians, myocardial regenerative responses in patients with STEMI and reduced ejection fraction showed no seem to be dependent on deposition of a specialized ECM (142). significant protection from adverse remodeling (132), despite A recent study reported that intramyocardial administration of significant antiremodeling effects in animal models. In contrast, ECM from healing zebrafish hearts may stimulate regeneration early nonselective MMP inhibition with doxycycline attenuated in mouse infarcts (143). Loss-of-function approaches suggested progression to dilative remodeling in patients with STEMI and that fibronectin deposition may be critical for regeneration of the left ventricular dysfunction (133). The conflicting findings may zebrafish heart (144). In newts, cardiac regeneration following reflect the pathophysiological heterogeneity of human myocar- injury was preceded by formation of a matrix network compris- dial infarction; successful implementation of matrix modulation ing tenascin-C, fibronectin, and hyaluronan. This specialized strategies may require development of biomarkers or imaging matrix network may serve as a path for progenitor cells as well as approaches to identify patients with specific alterations in matrix play an active role in activation of a regenerative program (145). metabolism (134). Moreover, interpretation of the effects of Considering that, much like in fish and amphibians, myocardi- therapies targeting MMPs are complicated by their wide range al infarction in mammals also induces a marked upregulation of actions beyond matrix metabolism involving processing and of tenascin-C and fibronectin without stimulating remuscular- modulation of bioactive cytokines and growth factors. ization, it is unlikely that matrix-dependent actions are suffi- Matrix-based interventions to modulate cellular cardiac cient to activate a regenerative program. Myocardial regenera- repair responses. Specialized matrix proteins and matricellular tion likely requires not only a “regenerative” matrix profile, but macromolecules critically modulate the cellular responses in also local secretion of a yet-undefined combination of cytokines the infarcted and remodeling heart and may hold the key for and growth factors, and activation of pathways that enhance development of new effective strategies to optimize repair and plasticity of progenitor cell populations (146). Third, in sever- to reduce adverse remodeling following cardiac injury. Ani- al cell therapy studies in mammalian models of cardiac injury, mal model studies have suggested that several members of the application of matrix-based patches containing progenitor cells matricellular family protect the infarcted heart from adverse showed enhanced effectiveness (147, 148). It has been suggested remodeling (12). Therapeutic approaches based on matricellu- that application of matrix patches that recapitulate the regener- lar proteins are particularly attractive because of the capacity ative environment of the embryonic myocardium may increase

jci.org Volume 127 Number 5 May 2017 1607 REVIEW The Journal of Clinical Investigation remuscularization following injury (149). Whether such effects electrical activity. Despite these problems, such matrix-driven may be due to direct actions of specific matrix proteins on car- strategies may represent the first step toward the generation of diac progenitors or reflect matrix-dependent activation of other functional human cardiac grafts. cell types (such as immune or vascular cells) remains unknown. Fourth, some experimental studies in mammals have suggest- Conclusions ed that matricellular macromolecules may induce proliferation All myocardial cells are enmeshed within a dynamic network of ECM of differentiated cardiomyocytes. Kühn and coworkers showed that not only serves a structural role and facilitates mechanical force that recombinant periostin administered as an epicardial Gel- transmission, but also regulates cell phenotype and function. Fol- foam patch following infarction improved cardiac function and lowing cardiac injury, changes in composition of the cardiac ECM attenuated cardiac remodeling, triggering cell cycle reentry in critically regulate inflammatory, reparative, fibrotic, and regenera- differentiated cardiomyocytes in an integrin-dependent manner tive responses. Over the last two decades, understanding of the biol- (150). Unfortunately, genetic manipulation of periostin expres- ogy of the cardiac matrix has expanded well beyond the early con- sion in mice did not support the proposed proliferative actions cepts focusing on the role of matrix proteins in cardiac mechanics. of periostin on cardiomyocytes (151). Whether modulation of the We now view the matrix as a dynamic entity that responds to injury matricellular protein profile following myocardial injury could by undergoing dramatic transformations. Release of bioactive frag- facilitate activation of a regenerative program in adult infarcted ments and incorporation of matricellular proteins expands the func- hearts remains unknown. tional repertoire of the matrix and drives repair by transducing key A growing body of experimental work attempts to exploit signals to many different cell types. Expansion of our knowledge on technological advances in perfusion-decellularization strate- the structure, proteomic profile, and functional properties of matrix gies (152) to generate scaffolds comprising human cardiac ECM constituents will enrich our understanding of the pathobiology of that may serve as tools for manufacture of cardiac grafts (153, heart disease, suggesting new therapeutic opportunities. 154). The acellular matrix obtained through decellularization could subsequently be used for recellularization with cardio- Acknowledgments myocytes derived from induced pluripotent stem cells (iPSCs) NGF’s laboratory is supported by NIH grants R01 HL76246 and R01 in order to generate myocardial-like structures. Early studies HL85440 and by grants PR151134 and PR151029 from the Depart- have generated tissue constructs with definitive sarcomeric ment of Defense Congressionally Directed Medical Research Pro- structure that exhibit contractile function and electrical con- grams (CDMRP). duction (153). Clearly, the current technology has significant limitations, and major advances are needed in order to pursue Address correspondence to: Nikolaos G. Frangogiannis, The Wilf clinical translation. Complete reendothelialization is necessary Family Cardiovascular Research Institute, Albert Einstein College to prevent activation of the coagulation system, generation of of Medicine, 1300 Morris Park Avenue, Forchheimer G46B, Bronx, functional valvular structures is critical for ventricular func- New York 10461, USA. Phone: 718.430.3546; E-mail: nikolaos. tion, and a conduction system is needed for transmission of [email protected].

1. Pinto AR, et al. Revisiting cardiac cellular compo- 2003;108(11):1395–1403. 17. Wang W, Sawicki G, Schulz R. Peroxynitrite- sition. Circ Res. 2016;118(3):400–409. 9. Weber KT. Cardiac interstitium in health and induced myocardial injury is mediated through 2. Kong P, Christia P, Frangogiannis NG. The disease: the fibrillar collagen network. J Am Coll matrix metalloproteinase-2. Cardiovasc Res. pathogenesis of cardiac fibrosis. Cell Mol Life Sci. Cardiol. 1989;13(7):1637–1652. 2002;53(1):165–174. 2014;71(4):549–574. 10. Frangogiannis NG. Pathophysiology of myocardi- 18. Alfonso-Jaume MA, et al. Cardiac ischemia- 3. Berk BC, Fujiwara K, Lehoux S. ECM remodel- al infarction. Compr Physiol. 2015;5(4):1841–1875. reperfusion injury induces matrix metallopro- ing in hypertensive heart disease. J Clin Invest. 11. Dobaczewski M, Gonzalez-Quesada C, Frangogi- teinase-2 expression through the AP-1 compo- 2007;117(3):568–575. annis NG. The extracellular matrix as a modula- nents FosB and JunB. Am J Physiol Heart Circ 4. Prabhu SD, Frangogiannis NG. The biological tor of the inflammatory and reparative response Physiol. 2006;291(4):H1838–H1846. basis for cardiac repair after myocardial infarc- following myocardial infarction. J Mol Cell Cardi- 19. Danielsen CC, Wiggers H, Andersen HR. Increased tion: from inflammation to fibrosis. Circ Res. ol. 2010;48(3):504–511. amounts of collagenase and gelatinase in porcine 2016;119(1):91–112. 12. Frangogiannis NG. Matricellular proteins in myocardium following ischemia and reperfusion. 5. Medugorac I, Jacob R. Characterisation of left cardiac adaptation and disease. Physiol Rev. J Mol Cell Cardiol. 1998;30(7):1431–1442. ventricular collagen in the rat. Cardiovasc Res. 2012;92(2):635–688. 20. Gearing AJ, et al. Matrix metalloproteinases 1983;17(1):15–21. 13. Murphy-Ullrich JE, Sage EH. Revisiting the and processing of pro-TNF-α. J Leukoc Biol. 6. Leonard BL, Smaill BH, LeGrice IJ. Structural matricellular concept. Matrix Biol. 2014;37:1–14. 1995;57(5):774–777. remodeling and mechanical function in heart 14. Cannon RO, et al. Early degradation of collagen 21. Van Lint P, Libert C. Chemokine and cytokine failure. Microsc Microanal. 2012;18(1):50–67. after acute myocardial infarction in the rat. Am J processing by matrix metalloproteinases and its 7. Bashey RI, Martinez-Hernandez A, Jimenez Cardiol. 1983;52(3):390–395. effect on leukocyte migration and inflammation. SA. Isolation, characterization, and localization 15. Whittaker P, Boughner DR, Kloner RA. Role of J Leukoc Biol. 2007;82(6):1375–1381. of cardiac collagen type VI. Associations with collagen in acute myocardial infarct expansion. 22. Feng G, Hao D, Chai J. Processing of CXCL12 other extracellular matrix components. Circ Res. Circulation. 1991;84(5):2123–2134. impedes the recruitment of endothelial pro- 1992;70(5):1006–1017. 16. Etoh T, et al. Myocardial and interstitial matrix genitor cells in diabetic wound healing. FEBS J. 8. Jugdutt BI. Ventricular remodeling after metalloproteinase activity after acute myocardial 2014;281(22):5054–5062. infarction and the extracellular collagen infarction in pigs. Am J Physiol Heart Circ Physiol. 23. Peng H, Wu Y, Duan Z, Ciborowski P, Zheng matrix: when is enough enough? Circulation. 2001;281(3):H987–H994. JC. Proteolytic processing of SDF-1α by matrix

1608 jci.org Volume 127 Number 5 May 2017 The Journal of Clinical Investigation REVIEW

metalloproteinase-2 impairs CXCR4 signaling in infarct healing by regulating the inflam- fibrin(ogen) binds growth factors and pro- and reduces neural progenitor cell migration. matory and fibrotic response. J Immunol. motes tissue repair when incorporated within Protein Cell. 2012;3(11):875–882. 2008;180(4):2625–2633. a synthetic matrix. Proc Natl Acad Sci U S A. 24. Denney H, Clench MR, Woodroofe MN. Cleav- 41. Trial J, et al. Fibronectin fragments modulate 2013;110(12):4563–4568. age of chemokines CCL2 and CXCL10 by matrix monocyte VLA-5 expression and monocyte 58. Rienks M, Papageorgiou AP, Frangogiannis NG, metalloproteinases-2 and -9: implications for migration. J Clin Invest. 1999;104(4):419–430. Heymans S. Myocardial extracellular matrix: chemotaxis. Biochem Biophys Res Commun. 42. Taylor KR, Trowbridge JM, Rudisill JA, Termeer an ever-changing and diverse entity. Circ Res. 2009;382(2):341–347. CC, Simon JC, Gallo RL. Hyaluronan fragments 2014;114(5):872–888. 25. Cox JH, Dean RA, Roberts CR, Overall CM. Matrix stimulate endothelial recognition of injury through 59. Schäfer BM, Maier K, Eickhoff U, Todd RF, Kram- metalloproteinase processing of CXCL11/I-TAC TLR4. J Biol Chem. 2004;279(17):17079–17084. er MD. Plasminogen activation in healing human results in loss of chemoattractant activity and 43. Teder P, et al. Resolution of lung inflammation by wounds. Am J Pathol. 1994;144(6):1269–1280. altered glycosaminoglycan binding. J Biol Chem. CD44. Science. 2002;296(5565):155–158. 60. Motley MP, et al. A CCR2 macrophage endocytic 2008;283(28):19389–19399. 44. Lindsey ML, et al. A novel collagen matric- pathway mediates extravascular fibrin clearance 26. Cauwe B, Opdenakker G. Intracellular substrate ryptin reduces left ventricular dilation in vivo. Blood. 2016;127(9):1085–1096. cleavage: a novel dimension in the biochemistry, post-myocardial infarction by promoting scar 61. Creemers E, et al. Disruption of the plasmin- biology and pathology of matrix metalloproteinas- formation and angiogenesis. J Am Coll Cardiol. ogen gene in mice abolishes wound healing es. Crit Rev Biochem Mol Biol. 2010;45(5):351–423. 2015;66(12):1364–1374. after myocardial infarction. Am J Pathol. 27. Schulz R. Intracellular targets of matrix metal- 45. O’Reilly MS, et al. Endostatin: an endogenous 2000;156(6):1865–1873. loproteinase-2 in cardiac disease: rationale and inhibitor of angiogenesis and tumor growth. Cell. 62. Brown LF, Dubin D, Lavigne L, Logan B, Dvorak therapeutic approaches. Annu Rev Pharmacol 1997;88(2):277–285. HF, Van de Water L. Macrophages and fibroblasts Toxicol. 2007;47:211–242. 46. Okada M, Oba Y, Yamawaki H. Endostatin stim- express embryonic fibronectins during cutaneous 28. Ali MA, Cho WJ, Hudson B, Kassiri Z, Gran- ulates proliferation and migration of adult rat wound healing. Am J Pathol. 1993;142(3):793–801. zier H, Schulz R. Titin is a target of matrix cardiac fibroblasts through PI3K/Akt pathway. 63. Ulrich MM, et al. Increased expression of metalloproteinase-2: implications in myocar- Eur J Pharmacol. 2015;750:20–26. fibronectin isoforms after myocardial infarction dial ischemia/reperfusion injury. Circulation. 47. Hamano Y, et al. Physiological levels of tum- in rats. J Mol Cell Cardiol. 1997;29(9):2533–2543. 2010;122(20):2039–2047. statin, a fragment of collagen IV α3 chain, are 64. Kanisicak O, et al. Genetic lineage tracing defines 29. Wells JM, Gaggar A, Blalock JE. MMP generated generated by MMP-9 proteolysis and suppress myofibroblast origin and function in the injured matrikines. Matrix Biol. 2015;44–46:122–129. angiogenesis via αVβ3 integrin. Cancer Cell. heart. Nat Commun. 2016;7:12260. 30. Gaggar A, Weathington N. Bioactive extracellular 2003;3(6):589–601. 65. Serini G, et al. The fibronectin domain ED-A is matrix fragments in lung health and disease. 48. Andersson L, et al. Rip2 modifies VEGF-induced crucial for myofibroblastic phenotype induction J Clin Invest. 2016;126(9):3176–3184. signalling and vascular permeability in myocardial by transforming growth factor-beta1. J Cell Biol. 31. Akthar S, et al. Matrikines are key regulators in ischaemia. Cardiovasc Res. 2015;107(4):478–486. 1998;142(3):873–881. modulating the amplitude of lung inflammation 49. Brown LF, et al. Expression of vascular permea- 66. Arslan F, et al. Lack of fibronectin-EDA promotes in acute pulmonary infection. Nat Commun. bility factor (vascular endothelial growth factor) survival and prevents adverse remodeling and 2015;6:8423. by epidermal keratinocytes during wound heal- heart function deterioration after myocardial 32. Adair-Kirk TL, Senior RM. Fragments of extracel- ing. J Exp Med. 1992;176(5):1375–1379. infarction. Circ Res. 2011;108(5):582–592. lular matrix as mediators of inflammation. Int J 50. Clark RA. Overview and general considerations of 67. Webber J, Meran S, Steadman R, Phillips Biochem Cell Biol. 2008;40(6–7):1101–1110. wound repair. In: Clark RA, Henson PM, eds. The A. Hyaluronan orchestrates transforming 33. Senior RM, Griffin GL, Mecham RP. Chemotactic Molecular and Cellular Biology of Wound Repair. New growth factor-β1-dependent maintenance activity of elastin-derived peptides. J Clin Invest. York, New York, USA: Plenum Press; 1988:3–33. of myofibroblast phenotype. J Biol Chem. 1980;66(4):859–862. 51. Flick MJ, et al. Leukocyte engagement of fibrin 2009;284(14):9083–9092. 34. Weathington NM, et al. A novel peptide CXCR (ogen) via the integrin receptor αMβ2/Mac-1 is 68. Hattori N, et al. Pericellular versican regulates ligand derived from extracellular matrix deg- critical for host inflammatory response in vivo. the fibroblast-myofibroblast transition: a role for radation during airway inflammation. Nat Med. J Clin Invest. 2004;113(11):1596–1606. ADAMTS5 protease-mediated proteolysis. J Biol 2006;12(3):317–323. 52. Corbett SA, Schwarzbauer JE. Fibronectin-fibrin Chem. 2011;286(39):34298–34310. 35. Gaggar A, et al. A novel proteolytic cascade gen- cross-linking: a regulator of cell behavior. Trends 69. Toeda K, et al. Versican is induced in infiltrating erates an extracellular matrix-derived chemoat- Cardiovasc Med. 1998;8(8):357–362. monocytes in myocardial infarction. Mol Cell Bio- tractant in chronic neutrophilic inflammation. 53. Smiley ST, King JA, Hancock WW. Fibrinogen chem. 2005;280(1-2):47–56. J Immunol. 2008;180(8):5662–5669. stimulates macrophage chemokine secre- 70. Bornstein P. Matricellular proteins: an overview. 36. Mydel P, et al. Neutrophil elastase cleaves laminin- tion through toll-like receptor 4. J Immunol. J Cell Commun Signal. 2009;3(3–4):163–165. 332 (laminin-5) generating peptides that are 2001;167(5):2887–2894. 71. Murphy-Ullrich JE. The de-adhesive activi- chemotactic for neutrophils. J Biol Chem. 54. Petzelbauer P, et al. The fibrin-derived pep- ty of matricellular proteins: is intermediate 2008;283(15):9513–9522. tide Bbeta15-42 protects the myocardium cell adhesion an adaptive state? J Clin Invest. 37. Villarreal F, Omens J, Dillmann W, Risteli against ischemia-reperfusion injury. Nat Med. 2001;107(7):785–790. J, Nguyen J, Covell J. Early degradation and 2005;11(3):298–304. 72. Bornstein P, Sage EH. Matricellular proteins: serum appearance of type I collagen fragments 55. Roesner JP, et al. The fibrin-derived peptide extracellular modulators of cell function. Curr after myocardial infarction. J Mol Cell Cardiol. Bbeta15-42 is cardioprotective in a pig model Opin Cell Biol. 2002;14(5):608–616. 2004;36(4):597–601. of myocardial ischemia-reperfusion injury. Crit 73. Mackie EJ, et al. Expression of tenascin by vascu- 38. Lauten A, Gerhard-Garcia A, Suhr F, Fischer JH, Care Med. 2007;35(7):1730–1735. lar smooth muscle cells. Alterations in hyperten- Figulla HR, Bloch W. Impact of ischemia-reper- 56. Atar D, et al. Effect of intravenous FX06 as sive rats and stimulation by angiotensin II. Am J fusion on extracellular matrix processing and an adjunct to primary percutaneous coronary Pathol. 1992;141(2):377–388. structure of the basement membrane of the intervention for acute ST-segment elevation 74. Hashimoto S, Suzuki T, Dong HY, Yamazaki N, heart. PLoS One. 2014;9(3):e92833. myocardial infarction results of the F.I.R.E. Matsushima K. Serial analysis of gene expression 39. Dobaczewski M, Bujak M, Zymek P, Ren G, Ent- (Efficacy of FX06 in the Prevention of Myocar- in human monocytes and macrophages. Blood. man ML, Frangogiannis NG. Extracellular matrix dial Reperfusion Injury) trial. J Am Coll Cardiol. 1999;94(3):837–844. remodeling in canine and mouse myocardial 2009;53(8):720–729. 75. Frangogiannis NG, et al. The critical role of infarcts. Cell Tissue Res. 2006;324(3):475–488. 57. Martino MM, Briquez PS, Ranga A, Lutolf endogenous Thrombospondin (TSP)-1 in pre- 40. Huebener P, et al. CD44 is critically involved MP, Hubbell JA. Heparin-binding domain of venting expansion of healing myocardial infarcts.

jci.org Volume 127 Number 5 May 2017 1609 REVIEW The Journal of Clinical Investigation

Circulation. 2005;111(22):2935–2942. 94. Zymek P, et al. The role of platelet-derived growth hypertrophy induced by pressure overload. J Clin 76. Willems IE, Arends JW, Daemen MJ. Tenascin factor signaling in healing myocardial infarcts. Invest. 1991;88(5):1737–1746. and fibronectin expression in healing human J Am Coll Cardiol. 2006;48(11):2315–2323. 111. Xia Y, et al. Endogenous thrombospondin 1 myocardial scars. J Pathol. 1996;179(3):321–325. 95. Davis GE, Norden PR, Bowers SL. Molecular con- protects the pressure-overloaded myocardium 77. Murry CE, Giachelli CM, Schwartz SM, Vracko trol of capillary morphogenesis and maturation by modulating fibroblast phenotype and matrix R. Macrophages express osteopontin during by recognition and remodeling of the extracel- metabolism. Hypertension. 2011;58(5):902–911. repair of myocardial necrosis. Am J Pathol. lular matrix: functional roles of endothelial cells 112. Konstandin MH, et al. Fibronectin contrib- 1994;145(6):1450–1462. and pericytes in health and disease. Connect utes to pathological cardiac hypertrophy but 78. Dewald O, et al. Of mice and dogs: species- Tissue Res. 2015;56(5):392–402. not physiological growth. Basic Res Cardiol. specific differences in the inflammatory response 96. Rivera LB, Brekken RA. SPARC promotes 2013;108(5):375. following myocardial infarction. Am J Pathol. pericyte recruitment via inhibition of endog- 113. Ulasova E, et al. Loss of interstitial collagen 2004;164(2):665–677. lin-dependent TGF-β1 activity. J Cell Biol. causes structural and functional alterations of 79. Trueblood NA, et al. Exaggerated left ventricular 2011;193(7):1305–1319. cardiomyocyte subsarcolemmal mitochondria dilation and reduced collagen deposition after 97. Sager HB, et al. Proliferation and recruit- in acute volume overload. J Mol Cell Cardiol. myocardial infarction in mice lacking osteopon- ment contribute to myocardial macrophage 2011;50(1):147–156. tin. Circ Res. 2001;88(10):1080–1087. expansion in chronic heart failure. Circ Res. 114. Chen YW, et al. Dynamic molecular and histo- 80. Schellings MW, et al. Absence of SPARC results 2016;119(7):853–864. pathological changes in the extracellular matrix in increased cardiac rupture and dysfunction 98. Chen B, Frangogiannis NG. Macrophages and inflammation in the transition to heart after acute myocardial infarction. J Exp Med. in the remodeling failing heart. Circ Res. failure in isolated volume overload. Am J Physiol 2009;206(1):113–123. 2016;119(7):776–778. Heart Circ Physiol. 2011;300(6):H2251–H2260. 81. Shimazaki M, et al. Periostin is essential for cardi- 99. Xia Y, Lee K, Li N, Corbett D, Mendoza L, Fran- 115. Hutchinson KR, Stewart JA Jr,Lucchesi PA. Extra- ac healing after acute myocardial infarction. gogiannis NG. Characterization of the inflam- cellular matrix remodeling during the progres- J Exp Med. 2008;205(2):295–303. matory and fibrotic response in a mouse model sion of volume overload-induced heart failure. 82. Oka T, et al. Genetic manipulation of periostin of cardiac pressure overload. Histochem Cell Biol. J Mol Cell Cardiol. 2010;48(3):564–569. expression reveals a role in cardiac hyper- 2009;131(4):471–481. 116. Fu L, Wei CC, Powell PC, Bradley WE, Collawn trophy and ventricular remodeling. Circ Res. 100. Abrahams C, Janicki JS, Weber KT. Myocardial JF, Dell’Italia LJ. Volume overload induces auto- 2007;101(3):313–321. hypertrophy in Macaca fascicularis. Structural phagic degradation of procollagen in cardiac fibro- 83. Kzhyshkowska J, et al. Novel function of alterna- remodeling of the collagen matrix. Lab Invest. blasts. J Mol Cell Cardiol. 2015;89(Pt B):241–250. tively activated macrophages: stabilin-1- 1987;56(6):676–683. 117. Chancey AL, Brower GL, Peterson JT, Janicki JS. mediated clearance of SPARC. J Immunol. 101. Herum KM, et al. Syndecan-4 is a key deter- Effects of matrix metalloproteinase inhibition on 2006;176(10):5825–5832. minant of collagen cross-linking and passive ventricular remodeling due to volume overload. 84. Aisagbonhi O, Rai M, Ryzhov S, Atria N, Feokti- myocardial stiffness in the pressure-overloaded Circulation. 2002;105(16):1983–1988. stov I, Hatzopoulos AK. Experimental myocar- heart. Cardiovasc Res. 2015;106(2):217–226. 118. Ryan TD, et al. Left ventricular eccentric remod- dial infarction triggers canonical Wnt signaling 102. Schwartzkopff B, Mundhenke M, Strauer BE. eling and matrix loss are mediated by bradyki- and endothelial-to-mesenchymal transition. Dis Remodelling of intramyocardial arterioles and nin and precede cardiomyocyte elongation in Model Mech. 2011;4(4):469–483. extracellular matrix in patients with arterial rats with volume overload. J Am Coll Cardiol. 85. Ubil E, et al. Mesenchymal-endothelial transi- hypertension and impaired coronary reserve. Eur 2007;49(7):811–821. tion contributes to cardiac neovascularization. Heart J. 1995;16(suppl I):82–86. 119. Borer JS, et al. Myocardial fibrosis in chronic Nature. 2014;514(7524):585–590. 103. Moore-Morris T, et al. Resident fibroblast lineag- aortic regurgitation: molecular and cellular 86. Zeisberg EM, et al. Endothelial-to-mesenchymal es mediate pressure overload-induced cardiac responses to volume overload. Circulation. transition contributes to cardiac fibrosis. Nat fibrosis. J Clin Invest. 2014;124(7):2921–2934. 2002;105(15):1837–1842. Med. 2007;13(8):952–961. 104. Ali SR, et al. Developmental heterogeneity 120. Russo I, Frangogiannis NG. Diabetes-associated 87. Saxena A, et al. IL-1 induces proinflammatory of cardiac fibroblasts does not predict patho- cardiac fibrosis: Cellular effectors, molecular leukocyte infiltration and regulates fibroblast logical proliferation and activation. Circ Res. mechanisms and therapeutic opportunities. J Mol phenotype in the infarcted myocardium. J Immu- 2014;115(7):625–635. Cell Cardiol. 2016;90:84–93. nol. 2013;191(9):4838–4848. 105. Kuster GM, et al. Mineralocorticoid receptor 121. Regan TJ, et al. Evidence for cardiomyopathy 88. Ren G, Michael LH, Entman ML, Frangogiannis inhibition ameliorates the transition to myocar- in familial diabetes mellitus. J Clin Invest. NG. Morphological characteristics of the micro- dial failure and decreases oxidative stress and 1977;60(4):884–899. vasculature in healing myocardial infarcts. inflammation in mice with chronic pressure over- 122. Hutchinson KR, Lord CK, West TA, Stewart J Histochem Cytochem. 2002;50(1):71–79. load. Circulation. 2005;111(4):420–427. JA. Cardiac fibroblast-dependent extracellular 89. Zhao W, Lu L, Chen SS, Sun Y. Temporal and 106. Grimm D, et al. Regulation of extracellular matrix matrix accumulation is associated with dia- spatial characteristics of apoptosis in the infarct- proteins in pressure-overload cardiac hypertro- stolic stiffness in type 2 diabetes. PLoS One. ed rat heart. Biochem Biophys Res Commun. phy: effects of angiotensin converting enzyme 2013;8(8):e72080. 2004;325(2):605–611. inhibition. J Hypertens. 1998;16(9):1345–1355. 123. Gonzalez-Quesada C, et al. Thrombospondin-1 90. Takemura G, et al. Role of apoptosis in the dis- 107. Nishida M, et al. P2Y6 receptor-Galpha12/13 induction in the diabetic myocardium stabilizes appearance of infiltrated and proliferated inter- signalling in cardiomyocytes triggers pressure the cardiac matrix in addition to promoting vas- stitial cells after myocardial infarction. Circ Res. overload-induced cardiac fibrosis. EMBO J. cular rarefaction through angiopoietin-2 upregu- 1998;82(11):1130–1138. 2008;27(23):3104–3115. lation. Circ Res. 2013;113(12):1331–1344. 91. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, 108. Yu Q, Horak K, Larson DF. Role of T lym- 124. Fischer VW, Barner HB, Larose LS. Pathomor- Brown RA. Myofibroblasts and mechano- phocytes in hypertension-induced cardiac phologic aspects of muscular tissue in diabetes regulation of remodelling. extracellular matrix remodeling. Hypertension. mellitus. Hum Pathol. 1984;15(12):1127–1136. Nat Rev Mol Cell Biol. 2002;3(5):349–363. 2006;48(1):98–104. 125. van Hoeven KH, Factor SM. A comparison of the 92. Hinz B. Formation and function of the myofi- 109. Laroumanie F, et al. CD4+ T cells promote the pathological spectrum of hypertensive, diabetic, broblast during tissue repair. J Invest Dermatol. transition from hypertrophy to heart failure and hypertensive-diabetic heart disease. Circula- 2007;127(3):526–537. during chronic pressure overload. Circulation. tion. 1990;82(3):848–855. 93. Bhattacharyya S, et al. Tenascin-C drives 2014;129(21):2111–2124. 126. Raman P, Krukovets I, Marinic TE, Bornstein P, persistence of organ fibrosis. Nat Commun. 110. Samuel JL, et al. Accumulation of fetal fibronec- Stenina OI. Glycosylation mediates up-regulation 2016;7:11703. tin mRNAs during the development of rat cardiac of a potent antiangiogenic and proathero-

1610 jci.org Volume 127 Number 5 May 2017 The Journal of Clinical Investigation REVIEW

genic protein, thrombospondin-1, by glucose 143. Chen WC, et al. Decellularized zebrafish cardiac infarction through infarct collagen strengthen- in cells. J Biol Chem. extracellular matrix induces mammalian heart ing. Circ Res. 2015;116(3):425–436. 2007;282(8):5704–5714. regeneration. Sci Adv. 2016;2(11):e1600844. 162. Zhou Y, Poczatek MH, Berecek KH, Murphy- 127. Clarke SA, Richardson WJ, Holmes JW. Mod- 144. Wang J, Karra R, Dickson AL, Poss KD. Fibronec- Ullrich JE. Thrombospondin 1 mediates angio- ifying the mechanics of healing infarcts: Is tin is deposited by injury-activated epicardial tensin II induction of TGF-β activation by cardiac better the enemy of good? J Mol Cell Cardiol. cells and is necessary for zebrafish heart regener- and renal cells under both high and low glucose 2016;93:115–124. ation. Dev Biol. 2013;382(2):427–435. conditions. Biochem Biophys Res Commun. 128. Silvestre JS, et al. Activation of cardiac aldoste- 145. Mercer SE, Odelberg SJ, Simon HG. A dynamic 2006;339(2):633–641. rone production in rat myocardial infarction: spatiotemporal extracellular matrix facilitates 163. Muñoz-Pacheco P, et al. Eplerenone enhanc- effect of angiotensin II receptor blockade epicardial-mediated vertebrate heart regenera- es cardioprotective effects of standard heart and role in cardiac fibrosis. Circulation. tion. Dev Biol. 2013;382(2):457–469. failure therapy through matricellular proteins 1999;99(20):2694–2701. 146. Uygur A, Lee RT. Mechanisms of cardiac regener- in hypertensive heart failure. J Hypertens. 129. Honda S, et al. Trends in the clinical and patho- ation. Dev Cell. 2016;36(4):362–374. 2013;31(11):2309–2319. logical characteristics of cardiac rupture in 147. Gaetani R, et al. Epicardial application of cardiac 164. Belmadani S, et al. A thrombospondin-1 antag- patients with acute myocardial infarction over 35 progenitor cells in a 3D-printed gelatin/hyaluronic onist of transforming growth factor-β activation years. J Am Heart Assoc. 2014;3(5):e000984. acid patch preserves cardiac function after myo- blocks cardiomyopathy in rats with diabetes 130. Hayashidani S, et al. Targeted deletion of cardial infarction. Biomaterials. 2015;61:339–348. and elevated angiotensin II. Am J Pathol. MMP-2 attenuates early LV rupture and late 148. Jang J, et al. 3D printed complex tissue construct 2007;171(3):777–789. remodeling after experimental myocardial using stem cell-laden decellularized extracellular 165. Schroen B, et al. Thrombospondin-2 is essen- infarction. Am J Physiol Heart Circ Physiol. matrix bioinks for cardiac repair. Biomaterials. tial for myocardial matrix integrity: increased 2003;285(3):H1229–H1235. 2017;112:264–274. expression identifies failure-prone cardiac hyper- 131. Holubec T, Caliskan E, Bettex D, Maisano F. 149. Serpooshan V, et al. Use of bio-mimetic three- trophy. Circ Res. 2004;95(5):515–522. Repair of post-infarction left ventricular free wall dimensional technology in therapeutics for heart 166. Swinnen M, et al. Absence of thrombospondin-2 rupture using an extracellular matrix patch. Eur J disease. Bioengineered. 2014;5(3):193–197. causes age-related dilated cardiomyopathy. Cir- Cardiothorac Surg. 2015;48(5):800–803. 150. Kühn B, et al. Periostin induces proliferation of culation. 2009;120(16):1585–1597. 132. Hudson MP, et al. Effects of selective matrix differentiated cardiomyocytes and promotes car- 167. Frolova EG, et al. Thrombospondin-4 regulates metalloproteinase inhibitor (PG-116800) to diac repair. Nat Med. 2007;13(8):962–969. fibrosis and remodeling of the myocardium prevent ventricular remodeling after myocardial 151. Lorts A, Schwanekamp JA, Elrod JW, Sargent MA, in response to pressure overload. FASEB J. infarction: results of the PREMIER (Prevention Molkentin JD. Genetic manipulation of periostin 2012;26(6):2363–2373. of Myocardial Infarction Early Remodeling) trial. expression in the heart does not affect myocyte 168. Mustonen E, et al. Thrombospondin-4 J Am Coll Cardiol. 2006;48(1):15–20. content, cell cycle activity, or cardiac repair. Circ expression is rapidly upregulated by cardi- 133. Cerisano G, et al. Early short-term doxycycline Res. 2009;104(1):e1–7. ac overload. Biochem Biophys Res Commun. therapy in patients with acute myocardial 152. Ott HC, et al. Perfusion-decellularized matrix: 2008;373(2):186–191. infarction and left ventricular dysfunction to using nature’s platform to engineer a bioartificial 169. Lynch JM, et al. A thrombospondin-dependent prevent the ominous progression to adverse heart. Nat Med. 2008;14(2):213–221. pathway for a protective ER stress response. Cell. remodelling: the TIPTOP trial. Eur Heart J. 153. Guyette JP, et al. Bioengineering human myo- 2012;149(6):1257–1268. 2014;35(3):184–191. cardium on native extracellular matrix. Circ Res. 170. Palao T, Rippe C, van Veen H, VanBavel E, 134. Frangogiannis NG. The inflammatory response in 2016;118(1):56–72. Swärd K, Bakker EN. Thrombospondin-4 myocardial injury, repair, and remodelling. Nat 154. Sánchez PL, et al. Acellular human heart matrix: knockout in hypertension protects small- Rev Cardiol. 2014;11(5):255–265. A critical step toward whole heart grafts. Bioma- artery endothelial function but induces aortic 135. Sawyer AJ, Kyriakides TR. Matricellular proteins terials. 2015;61:279–289. aneurysms. Am J Physiol Heart Circ Physiol. in drug delivery: Therapeutic targets, active 155. Frangogiannis NG, Mendoza LH, Lewallen M, 2016;310(11):H1486–H1493. agents, and therapeutic localization. Adv Drug Michael LH, Smith SW, Entman ML. Induction 171. Cingolani OH, et al. Thrombospondin-4 is Deliv Rev. 2016;97:56–68. and suppression of interferon-inducible pro- required for stretch-mediated contractility 136. Bergman O, et al. Evidence for cardio- tein-10 (IP-10) following experimental canine augmentation in cardiac muscle. Circ Res. myocyte renewal in humans. Science. myocardial infarction may regulate angiogene- 2011;109(12):1410–1414. 2009;324(5923):98–102. sis. FASEB J. 2001;15(8):1428–30. 172. Yamamoto K, Dang QN, Kennedy SP, Osath- 137. Laflamme MA, Murray CE. Heart regeneration. 156. Chablais F, Jazwinska A. The regenerative capac- anondh R, Kelly RA, Lee RT. Induction of Nature. 2011;473(7347):326–335. ity of the zebrafish heart is dependent on TGFβ tenascin-C in cardiac myocytes by mechanical 138. Matsa E, Sallum K, Wu JC. Cardiac stem cell biol- signaling. Development. 2012;139(11):1921–1930. deformation. Role of reactive oxygen species. ogy: glimpse of the past, present, and future. Circ 157. Tamaoki M, et al. Tenascin-C regulates J Biol Chem. 1999;274(31):21840–21846. Res. 2014;114(1):21–27. recruitment of myofibroblasts during tissue 173. Hessel M, Steendijk P, den Adel B, Schutte C, van 139. Karantalis V, Hare JM. Use of mesenchymal stem repair after myocardial injury. Am J Pathol. der Laarse A. Pressure overload-induced right cells for therapy of cardiac disease. Circ Res. 2005;167(1):71–80. ventricular failure is associated with re-expression 2015;116(8):1413–1430. 158. McCurdy SM, et al. SPARC mediates early extra- of myocardial tenascin-C and elevated plasma 140. Yahalom-Ronen Y, Rajchman D, Sarig R, Geiger cellular matrix remodeling following myocar- tenascin-C levels. Cell Physiol Biochem. 2009;24 B, Tzahor E. Reduced matrix rigidity promotes dial infarction. Am J Physiol Heart Circ Physiol. (3–4):201–210. neonatal cardiomyocyte dedifferentiation, 2011;301(2):H497–H505. 174. Shimojo N, et al. Tenascin-C may accelerate car- proliferation and clonal expansion. Elife. 159. Ahmed MS, et al. Mechanisms of novel cardio- diac fibrosis by activating macrophages via the 2015;4:e07455. protective functions of CCN2/CTGF in myocar- integrin αVβ3/nuclear factor-κB/interleukin-6 141. Qiu Y, et al. A role for matrix stiffness in the dial ischemia-reperfusion injury. Am J Physiol axis. Hypertension. 2015;66(4):757–766. regulation of cardiac side population cell Heart Circ Physiol. 2011;300(4):H1291–H1302. 175. Bradshaw AD, et al. Pressure overload-induced function. Am J Physiol Heart Circ Physiol. 160. Gravning J, et al. Myocardial connective tissue alterations in fibrillar collagen content and 2015;308(9):H990–H997. growth factor (CCN2/CTGF) attenuates left ven- myocardial diastolic function: role of secreted 142. Chablais F, Veit J, Rainer G, Jaźwińska A. The tricular remodeling after myocardial infarction. protein acidic and rich in cysteine (SPARC) in zebrafish heart regenerates after cryoinjury- PLoS One. 2012;7(12):e52120. post-synthetic procollagen processing. Circula- induced myocardial infarction. BMC Dev Biol. 161. Van Aelst LN, et al. Osteoglycin prevents cardiac tion. 2009;119(2):269–280. 2011;11:21. dilatation and dysfunction after myocardial 176. Harris BS, Zhang Y, Card L, Rivera LB, Brek-

jci.org Volume 127 Number 5 May 2017 1611 REVIEW The Journal of Clinical Investigation

ken RA, Bradshaw AD. SPARC regulates 2004;44(6):826–831. 182. López B, et al. Osteopontin-mediated myocardial collagen interaction with cardiac fibroblast 179. Singh K, et al. Myocardial osteopontin expression fibrosis in heart failure: a role for lysyl oxidase? cell surfaces. Am J Physiol Heart Circ Physiol. coincides with the development of heart failure. Cardiovasc Res. 2013;99(1):111–120. 2011;301(3):H841–H847. Hypertension. 1999;33(2):663–670. 183. Sam F, et al. Mice lacking osteopontin exhibit 177. Matsui Y, et al. Role of osteopontin in cardiac 180. Collins AR, et al. Osteopontin modulates angio- increased left ventricular dilation and reduced fibrosis and remodeling in angiotensin II- tensin II-induced fibrosis in the intact murine fibrosis after aldosterone infusion. Am J Hyper- induced cardiac hypertrophy. Hypertension. heart. J Am Coll Cardiol. 2004;43(9):1698–1705. tens. 2004;17(2):188–193. 2004;43(6):1195–1201. 181. Lorenzen JM, et al. Osteopontin is indispensible 184. Wang D, et al. Effects of pressure overload on 178. Xie Z, Singh M, Singh K. Osteopontin modu- for AP1-mediated angiotensin II-related miR-21 extracellular matrix expression in the heart of the lates myocardial hypertrophy in response to transcription during cardiac fibrosis. Eur Heart J. atrial natriuretic peptide-null mouse. Hyperten- chronic pressure overload in mice. Hypertension. 2015;36(32):2184–2196. sion. 2003;42(1):88–95.

1612 jci.org Volume 127 Number 5 May 2017