Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor Γ and Δ in Vascular Diseases Wai San Cheang, Bsc; Xi Fang, Bsc; Xiao Yu Tian, Phd

Advance Publication by-J-STAGE Circulation Journal REVIEW Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor γ and δ in Vascular Diseases Wai San Cheang, BSc; Xi Fang, BSc; Xiao Yu Tian, PhD

Peroxisome proliferator-activated receptors gamma (PPARγ) and delta (PPARδ) are nuclear receptors that have significant physiological effects on glucose and lipid metabolism. Experimental studies in animal models of metabolic disease have demonstrated their effects on improving lipid profile, insulin sensitivity, and reducing inflammatory responses. PPARγ and -δ are also expressed in the vasculature and their beneficial effects have been examined in various cardiovascular disease models such as atherosclerosis, hypertension, diabetic vascular complications, etc. using pharmacological ligands or genetic tools including viral vectors and transgenic mice. These studies suggest that PPARγ and δ are antiinflammatory, antiatherogenic, antioxidant, and antifibrotic against vascular diseases. Several signaling pathways, effector molecules, as well as coactivators/repressors have been identified as responsible for the protective effects of PPARγ and -δ in the vasculature. We discuss the pleiotropic effect of PPARγ and δ in vascular dysfunction, including atherosclerosis, hypertension, vascular remodeling, vascular injury, and diabetic vasculopathy, in various animal models, and the major underlying mechanisms. We also compare the pheno- types of several endothelial cell/vascular smooth muscle-specific PPARγ and -δ knockout and overexpressing transgenic mice in various disease models, and the implications underlying the functional importance of vascular PPARγ and δ in regulating whole-body homeostasis.

Key Words: Atherosclerosis; Endothelial function; Peroxisome proliferator-activated receptors; Vasculature

eroxisome proliferator-activated receptors (PPARs), leading to improved insulin sensitivity.6 PPARγ is also impli- including PPARα (NR1C1), PPARβ/δ (NR1C2) and cated in the regulation of lipid metabolism,7 as well as the P PPARγ (NR1C3), belong to the nuclear receptor su- maturation of monocytes/macrophages and the control of in- perfamily that functions as transcription factors to regulate flammatory reactions.8 In both humans and mice, loss-of-func- cellular differentiation, development and metabolism (carbohy- tion mutation of PPARγ is associated with insulin resistance and drate, lipid and protein). PPARα is predominantly expressed in diabetes.9,10 In addition, targeted deletion of PPARγ in skeletal cells with high rates of fatty acid catabolism such as those found muscle, macrophages, and adipose tissue suggests that PPARγ in liver, heart, kidney and skeletal muscle.1 PPARγ is mainly in these tissues regulates whole-body glucose homeostasis.11–13 associated with adipose tissue, playing a role in various physi- The function of PPARδ was first examined in globally ological and pathophysiological events, including adipocyte PPARδ-deficient mice and later studied using the recently differentiation2 and insulin sensitivity. PPARδ is abundantly developed synthetic PPARδ ligands. A high-affinity PPARδ and ubiquitously expressed at much higher levels than PPARγ ligand, GW501516, can reduce weight gain and reduce tri- and PPARα.3 Upon binding of its ligands, PPARs heterodimer- glycerides, and increase high-density lipoprotein (HDL) -cho- ize with the retinoid receptor (RXR) and bind to peroxisome lesterol in obese mice by increasing peripheral fatty acid ca- proliferator hormone responsive elements in the promoter re- tabolism.14,15 PPARδ also regulates glucose homeostasis. gion of the target genes to activate/repress transcription.4 En- GW501516 also lowers the plasma insulin level and improves dogenous ligands for the PPARs include free fatty acids and glucose tolerance and insulin sensitivity in diet-induced obese eicosanoids, and synthetic ligands for PPARγ and PPARδ have mice.16 Collectively, these findings suggest that PPARδ could been developed, targeting diabetes and dyslipidemia.5 be a potential therapeutic target for combating obesity and The biological functions of PPARγ and PPARδ have been insulin resistance. extensively studied in regard to metabolism. PPARγ activation In addition to a regulatory function in glucose and lipid enhances the lipid storage capacity of the adipose mass, and metabolism, PPARs are expressed in the cardiovascular sys- also increases the number of small, insulin-sensitive adipocytes, tem and their functions there have been shown to be most

Received June 7, 2013; revised manuscript received August 30, 2013; accepted September 19, 2013; released online October 10, 2013 Institute of Vascular Medicine and School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong (W.S.C., X.Y.T.); Institute of Cardiovascular Science, Peking University Health Science Center, Beijing (X.F.), China; and Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX (X.Y.T.), USA Mailing address: Xiao Yu Tian, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave. Houston TX 77030 USA. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-13-0647 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Advance Publication by-J-STAGE CHEANG WS et al. likely independent of their metabolic actions.17,18 PPARγ and inhibits the response of VSMC to inflammatory stimuli. Tumor PPARδ are expressed in endothelial cells (ECs) and vascular necrosis factor alpha (TNFα)-induced expression of chemo- smooth muscle cells (VSMCs). Here, we will focus on the role kines VCAM-1, MCP-1, and CX3CL1 can all be inhibited by of PPARγ and PPARδ in vascular biology beyond their regu- PPARγ activation in cultured VSMCs through inhibition of latory effects on glucose and lipid metabolism, and discuss NF-κB.33 Interleukin (IL)-1β-induced gene expression of COX2 their potential clinical implications. and IL-6 is inhibited by PPARγ activation through inhibition of DNA binding of NF-κB and C/EBP, thereby enhancing the 34,35 γ antiinflammatory effect of PPARγ. PPARγ agonists also Role of PPAR in ECs and VSMCs in Vitro suppress several growth factors, including platelet-derived PPARγ Activation in ECs growth factor (PDGF), basic fibroblast growth factor, throm- Inflammation PPARγ reduces the activation and inflam- bin, insulin, and AngII.36,37 Secondly, data show that inhibition mation of ECs by suppressing the expression of several proin- of PPARγ activity by point mutation directly promotes VSMC flammatory cytokines and chemokines through inhibition of the proliferation and migration.38 TZDs and the endogenous ligand nuclear factor kappa B (NF-κB), AP-1, protein kinase C (PKC) 15-d-PGJ2 also directly inhibit VSMC proliferation by decreas- signaling pathways, and oxidative stress components.19–21 Ei- ing the degradation of p27 (Kip1), an inhibitor of both CDK ther PPARγ agonist thiazolidinediones (TZDs) or overexpres- and phosphorylation of Rb, and thus prevent G1/S phase transi- sion of the constitutively active PPARγ can inhibit the expres- tion, causing cell cycle arrest.39 PPARγ activation inhibits sion of proinflammatory adhesion molecules and chemokines, VSMC migration through suppression of Ets-1 and matrix including intercellular adhesion molecule (ICAM-1), vascular metalloproteinase 9 (MMP9).40,41 PPARγ activation also sup- cell adhesion molecule (VCAM-1), E-selectin and monocyte presses telomerase activity and mini-chromosome maintenance chemotactic protein (MCP-1) in human ECs.19,20,22,23 In addi- proteins expression, thus regulating the replication and lifespan tion, TZDs inhibits the expressions of NADPH oxidase Nox-1, of VSMCs.42 In addition, rosiglitazone and troglitazone pro- 2 and 4, reducing the production of reactive oxygen species mote apoptosis of VSMC in a PPARγ-dependent manner via (ROS) and subsequent EC activation.24 Interestingly, PPARγ upregulation of growth arrest and DNA damage inducible gene can be also activated by laminar shear stress, which exerts an- 45 (GADD45), as well as p53 expression.43,44 tiinflammatory and antiatherogenic effects on ECs.25 Vasoreactivity The direct effect of PPARγ on VSMCs to Vasoreactivity Apart from antiinflammatory effects, PPARγ modulate vascular tone is associated with signaling pathways also modulates vascular tone through antagonizing the produc- related to AngII-induced vasoconstriction, including AT1R, tion or activation of vasoconstrictors, such as angiotensin II Ca2+ influx and Rho kinase activity. PPARγ inhibits AT1R and endothelin-1, while promoting vasodilatation, mainly by gene transcription by interaction with Sp1, thus reducing Sp1 increasing the production of vasodilating nitric oxide (NO).26 binding to the GC-box-related sequence in the AT1R promoter PPARγ agonist treatment increases NO release in human um- in VSMCs.45 PPARγ also regulates the expression of RGS5 by bilical vein ECs by enhancing the interaction of Hsp90 and binding to its promoter. RGS5 regulates PKC and BKCa chan- endothelial NO synthase (eNOS), resulting in increased eNOS nel activity in VSMCs, which is responsible for maintaining phosphorylation and activation, and the subsequent production myogenic tone in resistance arteries.46 In contrast, PPARγ li- of NO.27 In addition, PPARγ activation also enhances NO gands inhibit the Rho kinase pathway in VSMCs by upregulat- bioavailability by reducing endothelial oxidative stress.24 Con- ing SHP-2, which dephosphorylates Vav, a GTP/GDP exchange versely, NO can activate PPARγ in ECs through a p38-MAPK factor that upregulates Rho kinase activity.47 Furthermore, in dependent mechanism, suggesting a positive feedback loop large vessels, loss of PPARγ also leads to increased RhoA and between PPARγ and NO.28 Rho kinase activity and hypertension, because PPARγ directly Apart from enhancing vasodilation directly, PPARγ also controls expression of RhoBTB1 within the Cullin-3-RhoBTB1 antagonize potent vasoconstrictor endothelin-1 (ET-1). PPARγ complex that induces RhoA degradation.48 agonists also suppress the expression and secretion of ET-1 in 29 ECs by inhibiting the AP-1 transcriptional pathway. Apart In Vivo Effect of PPARγ Activation in from inducing vasoconstriction through binding to the ET-A receptor on VSMCs, ET-1 can also induce vasodilatation by Vascular Diseases (Figure 1) binding to the ET-B receptor (ETBR) on ECs and activating Phenotype of EC/VSMC-Specific PPARγ Knockout and eNOS, an effect more pronounced in resistance arteries. Impor- Mutation Mice tantly, PPARγ directly binds to the ETBR promoter and up- Disruption of endothelial PPARγ accelerates diet-induced ath- regulates ETBR, thus suppressing ET-1 induced vasoconstric- erogenesis in low-density lipoprotein receptor (LDLr)–/– mice.49 tion.30 In addition, PPARγ also antagonizes the vasoconstriction EC-specific PPARγ knockout (KO) mice also have exacerbated induced by angiotensin II (AngII). PPARγ activation inhibits lipopolysaccharide (LPS) -induced pulmonary inflammation AngII-induced vasoconstriction by increasing NO production. and injury as shown by increased infiltration of inflammatory Interestingly, 2 angiotensin-receptor blockers (ARBs), namely cells, edema, ROS and proinflammatory cytokine production.50 telmisartan and irbesartan, are also partial PPARγ agonists, Interestingly, mice with Tie2-Cre mediated EC-specific PPARγ thus some of the vasoprotective effects of telmisartan, and ir- deletion show significant dyslipidemia and lack of response to besartan, are dependent on activation of PPARγ, as demon- the free fatty acid (FFA) and triglyceride (TG) lowering effects strated by us and others.31,32 of the PPARγ agonist rosiglitazone, which indicates endothelial PPARγ integrates metabolic and vascular responses and Function of PPARγ in VSMCs may contribute to the in vivo effects of PPARγ agonists on Inflammation and Vascular Remodeling PPARγ activa- lipid metabolism, possibly because metabolic organs, includ- tion inhibits VSMC proliferation and migration through sev- ing muscle, fat and liver, are highly vascularized and micro- eral mechanisms, including direct inhibition of the production vascular ECs control fatty acid transport and uptake, TG me- of growth factors and proinflammatory cytokines, or regulation tabolism, and LDL function as well.51 These lines of evidence of genes controlling the cell cycle. Firstly, PPARγ activation concur with the in vitro data supporting antiinflammatory and Advance Publication by-J-STAGE PPARγ, PPARδ and Vascular Diseases

Figure 1. Schematic of the signaling pathways and cellular effects of peroxisome proliferator-activated receptor gamma (PPARγ). It can be activated by thiazolidinediones (TZDs) and endogenous ligands (L). Activation of PPARγ in endothelial cells (ECs) causes ETBR upregulation and nitric oxide (NO) release, while also inhibiting chemokines and adhesion molecule expression by repressing transcriptional activity of NF-κB/AP-1. In vascular smooth muscle cells (VSMCs), PPARγ activation inhibits contractile components, proliferation, and migration. eNOS, endothelial nitric oxide synthase; COX, cyclooxygenase; GADD, growth arrest and DNA damage inducible gene; ICAM, intercellular adhesion molecule; IL, interleukin; LDL, low-density lipoprotein; MCP, monocyte chemotactic protein; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PPRE, peroxisome proliferator hormone responsive element; NF-κB, nuclear factor kappa B; VCAM, vascular cell adhesion molecule.

anti-atherogenic functions of endothelial PPARγ, and a poten- cytes, causing impaired intravascular thermoregulation, endo- tial contributory role in lipid metabolism. thelial dysfunction, and exaggerated atherosclerosis.57 Together with the evidence from in vitro studies of VSMC, PPARγ also regulates vasomotor and inflammatory responses Effect of PPARγ Activation in Diabetic Vascular Function in the vasculature in vivo. Contraction of mouse aorta is reduced Evidence suggests that treatment with TZDs improves vascu- and vasodilatation is enhanced in response to β-adrenergic lar function in diabetic mice and humans. A 12-week treat- agonists in the aorta from VSMC-specific PPARγ KO mice, ment with rosiglitazone reduced plasma levels of C-reactive inducing a phenotype of biphasic response in blood pressure to protein (CRP) and increased the median coronary flow veloc- norepinephrine.52 However, overexpressing DN-PPARγ also ity reserve, which is an indicator of coronary endothelial func- caused increased Rho kinase activity in another study.48 It is tion, in patients with diabetes and coronary artery disease.58 thus possible that PPARγ interacts with different proteins in Pioglitazone treatment improved eNOS activity and enhanced conduit and resistance arteries in response to vasoactive stim- the vasodilatory response to acetylcholine in diabetic mice.59 uli to maintain vascular tone and blood pressure. In addition, Telmisartan, a partial PPARγ agonist, also protected against PPARγ has a clear role against vascular remodeling. Inducible diabetic vasculopathy in a mouse model of obesity and type 2 PPARγ KO in VSMCs exacerbated AngII-induced vascular diabetes, through normalizing of vascular PPARγ downregu- remodeling. Endothelium-dependent relaxation to acetylcho- lation in the diabetic mice.60 However, the in vivo effect of line was reduced in VSMC-specific PPARγ KO mice and fur- PPARγ activation by TZDs on endothelial function may be an ther impaired by AngII infusion, revealing the protective role indirect effect of improved glucose tolerance, insulin sensitiv- of VSMC PPARγ in AngII-induced vascular injury.53 Loss of ity, and increased vasoprotective adiponectin production in PPARγ in VSMC promotes transplantation-associated vascular diabetic mice.61 Rosiglitazone was withdrawn from the market lesion formation through increased VCAM-1 expression.54,55 because of increased risks of myocardial infarction or other Deletion of PPARγ in VSMCs also accelerates vascular calci- cardiovascular events based on several meta-analyses from fication in LDLr–/– mice, mediated through the secreted friz- randomized trials and Medicare databases.62,63 Such effects zled-related protein-2, which functions as a Wnt5a antagonist.56 may be related to some unknown genes that might be induced Interestingly, VSMC-specific PPARγ KO mice (SM22α-Cre) or repressed by either PPARγ or its coactivators/repressors show an unexpected phenotype of loss of perivascular adipo- in the transcriptional complex, which is yet to be discovered. Advance Publication by-J-STAGE CHEANG WS et al.

Moreover, in experimental settings, the effects of PPARγ on the in all types of cells, including ECs and VSMCs.80,81 In ECs, vascular system are only observed over a short period in rodent PPARδ activation inhibits inflammation, oxidative stress, and studies aiming at understanding the biology of PPARγ in vas- apoptosis; while stimulating angiogenesis. In human ECs, the culature, so we cannot exclude the possibility of any unknown PPARδ ligands, L-165041, GW0742 and GW501516, attenu- causes that are responsible for the adverse effect of PPARγ on ate inflammatory responses by reducing the translocation of the cardiovascular outcomes in type 2 diabetic patients. NF-κB and the subsequent expression of VCAM-1, ICAM-1, E-selectin, MCP-1 and growth-regulated oncogene alpha Role of PPARγ in Atherosclerosis (GROα).82–84 Apart from its ability to suppress proinflamma- The antiatherogenic effects of PPARγ agonists have been dem- tory adhesion molecules and chemokines, GW0742 also pro- onstrated in LDLr–/–, and ApoE–/– mouse models, and hu- tects ECs against oxidative stress by upregulation of antioxi- mans.64 Li et al demonstrated that rosiglitazone or GW7845 dant enzymes, including superoxide dismutase-1, catalase and reduced the development of atherosclerosis in male LDLr–/– thioredoxin reductase.85 Importantly, an endogenous ligand mice.65 The atheroprotective effect of troglitazone was ob- for PPARδ is prostacyclin (PGI2), which can be released by served in ApoE–/– mice,66 and also in high fructose- or high the endothelium. Besides its vasodilatory and antiaggregating fat-fed mice.67 Adenoviral overexpression of PPARγ1 can in- functions, prostacyclin also enhances the proangiogenic func- duce caveolin-1 expression and enhance macrophage choles- tion of human and mouse endothelial progenitor cells through terol efflux, thus attenuate atherosclerosis in ApoE–/– mice.68 PPARδ.86,87 Prostacyclin and L-165041 both can prevent H2O2- Likewise, inhibition of PPARγ exaggerates atherosclerosis. induced apoptosis in human ECs by inducing the binding of Bone marrow transplantation from PPARγ null mice to LDLr–/– PPARδ to the 14-3-3α promoter, which augments proapoptotic mice resulted in an increase in atheroma formation.69 Bone Bcl-2 protein Bad sequestration and reduces Bad translocation marrow reconstitution with macrophage-specific KO of PPARγ to mitochondria to prevent initiation of the death signal.88 also exacerbated atherogenesis, by increasing macrophage re- cruitment.70 In addition to its ability to reduce plaque forma- PPARδ in VSMCs tion, PPARγ also promotes plaque stability. Rosiglitazone can Similar to PPARγ, PPARδ also exerts an antiproliferative effect modify plaque composition and decrease the number of buried on VSMCs. PPARδ activation blocks cell cycle progression fibrous caps to stabilize vulnerable plaques in ApoE–/– mice.71 and reduces VSMC proliferation. L-165041 inhibits PDGF- Pioglitazone reduces MMP expression and macrophage ac- induced VSMC proliferation and neointimal formation after tivity in carotid plaques from ApoE–/– mice, confirming the carotid injury in rats by inhibiting cyclin D1 and cyclin-depen- plaque-stabilizing effect of PPARγ activation.72 Such effects dent kinase 4 (CDK4) expression and decreasing the phos- are also verified using adenovirus-mediated overexpression of phorylation of the retinoblastoma tumor suppressor protein,89 PPARγ in ApoE–/– mice, including reduced lipid deposition, while GW501516 reduces IL-1β-induced proliferation and mi- and reduced macrophage number, increased collagen and SMCs gration of rat aortic VSMCs through increase expression of p53 in the plaques, accompanied by decreased MMP-9, tissue fac- and p21.90 PPARδ activation also induces cell cycle inhibitors tor, MCP-1.73 Therefore, PPARγ is atheroprotective during p21 and p27 in rat aortic VSMCs.91 In addition, GW501516 different stages of plaque formation by enhancing cholesterol exerts antiinflammatory92 and antiapoptotic effects93 in murine efflux, reducing macrophage number, reducing extracellular aortic VSMCs, through its direct target gene TGFβ1. matrix reaction, and stabilizing vulnerable plaques. In Vivo Effect of PPARδ Activation in Effect of PPARγ Against Hypertension Genetic analysis shows that 2 dominant negative mutations in Vascular Diseases (Figure 2) PPARγ are associated with severe hypertension in humans,9 Effect of PPARδ in Metabolic Disease indicating an important role of PPARγ in blood pressure regula- Existing evidence indicates that PPARδ activation exerts ben- tion. PPARγ agonists lower blood pressure in diabetic mice.74–76 eficial effects on lipid and glucose metabolism in mouse mod- We showed that rosiglitazone attenuated ET-1-induced vaso- els of obesity and diabetes. GW501516 or overexpression of constriction and enhanced the ET-1-mediated vasodilating ef- PPARδ reduces weight gain and circulating TG level, while fect through upregulation of ETBR expression in mouse aortas increasing HDL in high fat diet-induced obese mice, db/db, and and mesenteric arteries, which may contribute to the regulation ob/ob mice through stimulating peripheral fatty acid catabo- of vascular tone in hypertension by PPARγ agonists.30 We also lism.14–16,94 In obese mice, administration of GW501516 low- showed that PPARγ ameliorates hyperreactivity of the pulmo- ers the plasma insulin level and improves insulin sensitivity by nary artery and thus inhibits vascular remodeling in rat models enhancing glucose consumption and fatty acid synthesis in the of pulmonary arterial hypertension. PPARγ activation inhibits liver.15,16 Both GW0742 treatment and hepatic overexpression 5-HT 2B receptor expression by inhibiting 5-HT-induced AP- of PPARδ rescue hepatic steatosis by inhibiting lipogenesis in 1/c-jun binding to AP-1 responsive elements in the 5-HT2BR obese diabetic mice.95 promoter, thus suppressing the effect of 5-HT on the pulmonary vasculature.77 Pioglitazone also attenuates vascular fibro- PPARδ Against Endothelial Dysfunction sis and improves vascular function in spontaneously hyperten- GW0742 and L-165041 at higher concentrations (>1 μmol/L) sive rats78 through increasing COX-2-derived prostaglandin I2 are reported to directly induce endothelium-dependent relax- (PGI2) production, reducing oxidative stress, leading to in- ation, eNOS phosphorylation and NO production in rat aorta, creased NO bioavailability and thus to improved vasodilation through activation of the phosphatidylinositol 3-kinase (PI3K)/ in resistance arteries.79 Akt pathway.96 Administration of GW0742 in vivo restores endothelial function in streptozotocin-induced type 1 diabetic rats by increasing NO bioavailability, as well as decreasing Role of PPARδ in ECs and VSMCs in Vitro NADPH oxidase-driven superoxide production.97 Moreover, PPARδ in ECs our recent study demonstrated that another PPARδ agonist, PPARβ/δ (NR1C2) is abundantly and ubiquitously expressed GW501516, restores endothelial dysfunction in the aorta and Advance Publication by-J-STAGE PPARγ, PPARδ and Vascular Diseases

Figure 2. Schematic showing the effect of proliferator-activated receptor delta (PPARδ) in the vasculature. Upon activation in endothelial cells (ECs), PPARδ also exhibits antiinflammatory effects through targeting NF-κB. PPARδ activation also upregulates antioxidant enzymes, and activates the PI3K pathway to enhance nitric oxide (NO) production. In vascular smooth muscle cells (VSMCs), PPARδ activation inhibits cell proliferation by repressing cell cycle components. eNOS, endothelial nitric oxide synthase; GROα, growth-regulated oncogene alpha; HDL, high-density lipoprotein; ICAM, intercellular adhesion molecule; IL, interleukin; LDL, low-density lipoprotein; PPRE, peroxisome proliferator hormone responsive element; VCAM, vascular cell adhesion molecule.

mesenteric resistance arteries of diabetic db/db mice and diet- of PPARδ ameliorates the dyslipidemia that is recognized as induced obese mice through enhancing PI3K/Akt signaling with the major contributor to atherosclerosis susceptibility. In line subsequent increases in eNOS activity and NO production.98 with the evidence from in vitro studies of ECs and VSMCs, PPARδ agonists were found to reduce atherosclerotic lesion PPARδ Against Hypertension area through antiinflammatory mechanisms in both ApoE–/– The effect of PPARδ ligands in hypertension has also been and LDLr–/– mice.103–105 PPARδ activation suppresses the ex- examined. In hypertensive rats, administration of GW0742 pression of ICAM-1 and MCP-1 in the mouse aorta and TNFα decreases systolic blood pressure, mesenteric vascular hyper- expression in macrophages, thus reducing atherosclerosis in trophy, and endothelial dysfunction, accompanied by an in- LDLr–/– mice.105 Notably, selective deletion of PPARδ in mac- crease in eNOS activity and decreased NADPH oxidase activ- rophages attenuates atherosclerosis in LDLr–/– mice.106 This ity and expression of proinflammatory and proatherogenic unexpected observation can be explained by the physical inter- genes, which is similar to the effect of PPARγ.99 Additionally, action between PPARδ and Bcl-6. Bcl-6 is not sequestered in GW501516 and L-165041 enhance the recovery of blood flow the absence of PPARδ and thus suppresses the transcription of in mice after hind limb ischemia and stimulate the prolifera- proatherogenic genes such as MCP-1. tion of endothelial progenitor cells by acting on the PI3K/Akt Recently, the effects of several PPARδ or dual PPARα/δ pathway.100 In general, PPARδ activation is beneficial for agonists have been examined in small-scale clinical trials. vascular function. PPARδ agonist, MBX-8025, improved the lipid profile and reduced the CRP level in overweight dyslipidemia subjects.107,108 PPARδ Against Atherosclerosis Similar effects were also observed with GW501516 in subjects Various lines of evidence show that PPARδ may retard the with metabolic syndrome.101,109,110 Dual PPARα/δ agonist, development and progression of atherosclerosis through mod- GFT505, improves both lipid and glucose metabolism in pa- ulating lipid metabolism in different tissues and exerting an tients with central obesity, dyslipidemia, and impaired glucose antiinflammatory effect through macrophages. PPARδ agonists metabolism.101,111 Although no adverse effect has been found normalize the levels of HDL, LDL and TG in obese and dia- in these clinical trials, GW501516 may have increased the betic animal models as well as in obese men.14–16,94,101 Impor- incidence of adenoma in a mouse model of colorectal can- tantly, PPARδ acts as sensor for very low-density lipoprotein cer.112,113 The safety of PPARδ needs to be further evaluated (VLDL), regulating TG homeostasis locally in peripheral tis- before it can be used to treat metabolic disease. sues such as macrophages and vessel walls.102 The activation Advance Publication by-J-STAGE CHEANG WS et al.

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