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The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

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The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling cells Review The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling Cristina Rodríguez 1,2,3,* and José Martínez-González 2,3,4,* 1 Institut de Recerca Hospital de la Santa Creu i Sant Pau-Programa ICCC, 08025 Barcelona, Spain 2 Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau), 08041 Barcelona, Spain 3 CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain 4 Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain * Correspondence: [email protected] (C.R.); [email protected] (J.M.-G.); Tel.: +34-93-556-5897 (C.R.); +34-93-556-5896 (J.M.-G.) Received: 29 October 2019; Accepted: 20 November 2019; Published: 21 November 2019 Abstract: Lysyl oxidase (LOX) proteins comprise a family of five copper-dependent enzymes (LOX and four LOX-like isoenzymes (LOXL1–4)) critical for extracellular matrix (ECM) homeostasis and remodeling. The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter- and intra-catenary covalent cross-linkages. Therefore, they are essential for the synthesis of a mature ECM and assure matrix integrity. ECM modulates cellular phenotype and function, and strikingly influences the mechanical properties of tissues. This explains the critical role of these enzymes in tissue homeostasis, and in tissue repair and remodeling. Cardiac ECM is mainly composed of fibrillar collagens which form a complex network that provides structural and biochemical support to cardiac cells and regulates cell signaling pathways. It is now becoming apparent that cardiac performance is affected by the structure and composition of the ECM and that any disturbance of the ECM contributes to cardiac disease progression. This review article compiles the major findings on the contribution of the LOX family to the development and progression of myocardial disorders. Keywords: lysyl oxidases; cardiac function; myocardial hypertrophy; extracellular matrix remodeling 1. Introduction Lysyl oxidase (LOX) proteins comprise a family of copper-dependent enzymes which governs extracellular matrix (ECM) homeostasis and remodeling. Five highly homologous LOX proteins have been identified in mammals: LOX and four LOX-like isoenzymes (LOXL1–4). The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter- and intra-catenary covalent cross-linkages [1,2]. In the adult mammalian heart, an intricate network of ECM proteins provides a scaffold for the cellular components and participates in the transmission of contractile forces. Studies in both humans and in animal models have evidenced that the abnormal expression/activity of LOX/LOXLs isoenzymes is linked to cardiovascular diseases [1,3,4]. Excessive myocardial collagen deposition and cross-linking (CCL), a process conditioned by LOX enzymes, contributes to cardiac fibrosis and determines left ventricular (LV) stiffness and dysfunction [5–7]. Essentially, fibrosis is characteristic of all forms of heart disease, and most of the pathophysiological stimuli that trigger cardiac fibrosis modulate LOX/LOXLs, playing a critical role in the process [8–10]. Beyond CCL, additional biological functions have been reported for LOX/LOXLs [1,2]. Further, genes encoding LOX enzymes are Cells 2019, 8, 1483; doi:10.3390/cells8121483 www.mdpi.com/journal/cells Cells 2019, 8, 1483 2 of 20 Cells 2019, 8, 1483 2 of 20 functions have been reported for LOX/LOXLs [1,2]. Further, genes encoding LOX enzymes are part partof the of themechanoresponsive mechanoresponsive gene gene programs programs responsible responsible for for the the mechanical mechanical regulation ofof genegene expressionexpression inin cardiaccardiac myocytesmyocytes andand fibroblastsfibroblasts [[11].11]. Thus,Thus, LOXLOX/LOXLs/LOXLs contributecontribute toto cardiaccardiac fibrosis,fibrosis, butbut areare also also active active players players involved involved inin the the cellular cellular mechanisms mechanisms underlyingunderlying cardiaccardiac dysfunctiondysfunctionand and diseasedisease progression. progression. InIn the the last last years, years multiple, multiple studies havestudies contributed have contributed to the understanding to the ofunderstanding the pathophysiological of the rolepathophysiological of the LOX family role of inthe human LOX family diseases in human and, diseases in particular, and, in inparticular, the cardiovascular in the cardiovascular system. Thesystem. involvement The involvement of this of family this family on vascular on vascular diseases diseases has has been been recently recently reviewed reviewed [12 [12].]. Further,Further, LOXLOX/LOXLs/LOXLs participateparticipate in in a a variety variety of of processes processes affec afftingecting the the heart, heart, from from those those associated associated to post to- post-myocardialmyocardial infarction infarction (MI) cardiac (MI) cardiac remodeling, remodeling, cardiac cardiachypertrophy hypertrophy triggered triggered by pressure by or pressure volume oroverload, volume overload,heart failure heart (HF) failure with (HF) preserved with preserved ejection ejection fraction fraction (HFPEF) (HFPEF) associated associated with withobesity obesity and andmetabolic metabolic syndrome syndrome or atrial or atrial fibrillation. fibrillation. The Thestrong strong impact impact of the of alteration the alteration of LOX/LOXLs of LOX/LOXLs on CCL on CCLand andheart heart function function supports supports the the interest interest of ofthese these family family of of enzymes enzymes as as pharmacological targetstargets toto improveimprove cardiac cardiac remodeling remodeling and and slow slow the the progression progression to to HF. HF. In In this this review review article article we we focus focus on on those those findingsfindings that that support support the the fundamental fundamental involvement involvement of of the the LOX LOXfamily familyin in thethe mechanismsmechanismsunderlying underlying cardiaccardiac damage damage and and repair. repair. 2.2. TheThe LOXLOX FamilyFamily ofof ECM-ModifyingECM-Modifying EnzymesEnzymes LOXLOX isis anan extracellularextracellular enzymeenzyme whichwhich governsgoverns thethe post-translationalpost-translational modificationmodification ofof ECMECM collagencollagen and and elastin. elastin. LOX LOX catalyzes catalyzes the the oxidative oxidative deamination deamination of specificof specific"-amino ε-amino groups groups of lysine of lysine and hydroxylysineand hydroxylysine residues residues in collagen in collagen and elastin. and elastin. This leads This to leads the generation to the generation of highly of reactive highly peptidyl reactive αpeptidyl-aminoadipic α-aminoadipicγ-semialdehydes γ-semialdehydes and the release and the of hydrogenrelease of peroxidehydrogen as peroxide by-product as by [1-–product3] (Figure [11–).3] This(Figure reaction 1). This allows reaction the covalent allows the cross-linking covalent cross of collagen-linking and of collagen elastin, whichand elastin, ensures which the appropriate ensures the tensileappropriate strength tensile and elasticstrength properties and elastic of connectiveproperties of tissues. connective tissues. Figure 1. The reaction catalyzed by LOX. LOX activity allows the oxidation of peptidyl lysine residues Figure 1. The reaction catalyzed by LOX. LOX activity allows the oxidation of peptidyl lysine residues in collagen and elastin chains to the corresponding peptidyl aldehydes. in collagen and elastin chains to the corresponding peptidyl aldehydes. LOX is the archetypal member of this family that comprises five closely related copper-dependent LOX is the archetypal member of this family that comprises five closely related copper- enzymes: LOX and four LOX-like isoenzymes (LOXLs: LOXL1, LOXL2, LOXL3, and LOXL4) [13]. dependent enzymes: LOX and four LOX-like isoenzymes (LOXLs: LOXL1, LOXL2, LOXL3, and Although they are product of distinct genes, all of them show a highly conserved catalytic domain LOXL4) [13]. Although they are product of distinct genes, all of them show a highly conserved and diverge in the rest of the sequence. Indeed, this family possesses a conserved carboxyl-terminal catalytic domain and diverge in the rest of the sequence. Indeed, this family possesses a conserved (C-terminal) amine oxidase catalytic domain, which comprises a His-X-His-X-His copper-binding carboxyl-terminal (C-terminal) amine oxidase catalytic domain, which comprises a His-X-His-X-His motif and the lysine tyrosyl quinone (LTQ) cofactor. By contrast, the amino-terminal (N-terminal) copper-binding motif and the lysine tyrosyl quinone (LTQ) cofactor. By contrast, the amino-terminal domains of these enzymes are structurally unrelated and their biological role is largely unknown. (N-terminal) domains of these enzymes are structurally unrelated and their biological role is largely Based on the primary structure of their N-termini, the family can be divided in two subgroups: LOX unknown. Based on the primary structure of their N-termini, the family can be divided in two and LOXL1, which contain a highly basic pro-peptide (PP) sequence, and LOXL2, LOXL3 and LOXL4 subgroups: LOX and LOXL1, which contain a highly basic pro-peptide (PP) sequence, and LOXL2, which
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