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• W2114098473 abstract "HomeCirculation ResearchVol. 104, No. 1Suppression of Peroxisome Proliferator-Activated Receptor-γ Activity by Angiotensin II in Vascular Smooth Muscle Involves Bcr Kinase Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSuppression of Peroxisome Proliferator-Activated Receptor-γ Activity by Angiotensin II in Vascular Smooth Muscle Involves Bcr KinaseThe Fire That Drowns The Water Ernesto L. Schiffrin and Pierre Paradis Ernesto L. SchiffrinErnesto L. Schiffrin From the Lady Davis Institute for Medical Research (E.L.S., P.P.) and Department of Medicine (E.L.S.), Sir Mortimer B. Davis–Jewish General Hospital, McGill University, Montreal, Quebec, Canada. Search for more papers by this author and Pierre ParadisPierre Paradis From the Lady Davis Institute for Medical Research (E.L.S., P.P.) and Department of Medicine (E.L.S.), Sir Mortimer B. Davis–Jewish General Hospital, McGill University, Montreal, Quebec, Canada. Search for more papers by this author Originally published2 Jan 2009https://doi.org/10.1161/CIRCRESAHA.108.191155Circulation Research. 2009;104:4–6Peroxisome proliferator activator receptors (PPARs) are nuclear receptors that exert effects on lipid and carbohydrate metabolism. Three members of the PPAR family have been identified: α, β/δ, and γ. PPAR-α and PPAR-β/δ regulate genes that play a role in lipid metabolism and fatty acid oxidation. PPAR-γ is expressed mostly in adipose tissue, controls adipocyte differentiation and lipid storage, and sensitizes tissues to the action of insulin. PPAR-γ is also abundantly expressed in the arterial tree. Natural ligands of PPAR-γ include free fatty acids and prostaglandin D2 derivatives such as 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2). Synthetic ligands for PPAR-γ include the thiazolidinediones (glitazones), which are insulin sensitizers used for treatment of diabetes mellitus. Activation of PPAR-γ with thiazolidinediones has been shown to result in abrogation of effects of angiotensin (Ang) II in rats. PPAR-γ ligands (rosiglitazone and pioglitazone) prevented development of hypertension in Ang II–infused rats, regressed vascular remodeling, reduced vascular inflammation, and improved endothelial function.1 Vascular DNA synthesis, nuclear factor (NF)-κB activity and expression of cell cycle proteins, Ang II type 1 receptors, vascular cell adhesion molecule (VCAM)-1, and platelet and endothelial cell adhesion molecule (PECAM), which were increased by Ang II infusion, were blunted by pioglitazone or rosiglitazone. This suggested that PPAR-γ could act as an endogenous Ang II antagonist, modulating the effects of the renin–angiotensin–aldosterone system. Similar effects were found in a mineralocorticoid hypertensive model, the deoxycorticosterone (DOCA)-salt rat, which is associated with activation of the endothelin system and in which the effects of PPAR-γ ligands like rosiglitazone on remodeling, oxidative stress, and inflammatory mediators could also be attributed to abrogation of mineralocorticoid and endothelin-1 actions.2 To exert their metabolic effects, PPARs function through transcriptional regulation of numerous genes by acting in association with retinoid X receptor-α and corepressors and coactivators on a PPAR response element. The cardiovascular and antiinflammatory actions of PPARs, including PPAR-γ, however, appear to occur through transrepression of proinflammatory and growth promoting genes.3,4Understanding the interactions of Ang II with PPAR-γ requires knowledge of the molecular and cellular mechanisms whereby PPAR-γ may induce growth arrest or apoptosis,5 as well as antiinflammatory effects. PPAR-γ may contribute to induce a differentiated phenotype in proliferating vascular smooth muscle cells (VSMCs) by transactivation of smooth muscle myosin heavy chain and α-actin genes.6 PPAR-γ ligands modulate DNA replication and cell cycle progression in VSMCs.7 Thiazolidinediones prevent VSMC proliferation through blockade of the activity of regulatory proteins, such as phosphorylation of the retinoblastoma protein (Rb), which controls gene expression mediated by the E2F transcription factor in the S phase of the cell cycle.8 PPAR-γ ligands increase levels of the cyclin-dependent kinase inhibitor p27kip1 and reduce the activity of cyclin D– and cyclin E–dependent kinases, leading to cell cycle arrest. Glitazones also inhibit the induction of minichromosome maintenance proteins 6 and 7, two E2F-regulated S phase genes essential for DNA replication.9 The PPAR-γ ligands 15d-PGJ2 and rosiglitazone blunt Ang II–mediated cell growth by interfering with phosphatidylinositol 3-kinase activity.10 This occurs through phosphorylation (and inhibition) of SHIP2 (Src homology 2-containing inositol phosphatase 2) activity, which reduces the bioactive phospholipids produced by phosphatidylinositol 3-kinase that stimulate Akt/protein kinase B and p70 S6 kinase, and by inhibition of the mTOR (mammalian target of rapamycin) substrate eukaryotic initiation factor 4E-BP1 (4E-binding protein 1)10 that would have an effect further downstream to inhibit protein synthesis and cell growth. PPAR-γ ligands not only inhibit cell growth but can also induce apoptosis in VSMCs by increasing expression of the GADD45 (growth arrest and DNA damage-inducible 45) gene.11 PPAR-γ also downregulates subsets of Toll-like receptor target genes in macrophages and may regulate the activity of dendritic cells, resulting in nonreactive CD4+ T cells, which contribute to their antiinflammatory actions.PPAR-γ induces transrepression of proinflammatory mediators in large part via its effects on NF-κB and activator protein-1 through different mechanisms (Figure). On PPAR-γ ligand binding, the nuclear receptor is conjugated with SUMO1 (small ubiquitin-like modifier 1) on lysine 365 via the action of E2 ligase Ubc9 and E3 ligase PIAS1. Sumoylation of PPAR-γ interferes with heterodimerization with retinoid X receptor, resulting in PPAR-γ being dedicated to the transrepression pathway. The complex may then repress gene transcription by inhibiting the release of the corepressor NCoR/histone deacetylase 3 complex from the promoter of inflammatory genes to the 19S proteasome, with the result being transrepression of proinflammatory or growth promoting gene transcription.12 Another potential mechanism involves CCAAT/enhancer-binding protein (C/EBP)-δ, which binds to response elements present in tandem repeats in the PPAR-γ gene promoter and induces expression of inflammatory cytokines but is inhibited by transactivation by PPAR-γ in the vasculature.13 PPAR-γ ligands may also bind to C/EBP-β14 or inhibit binding of NF-κB and C/EBP-β to the interleukin-6 promoter, inducing inhibition of proinflammatory responses.15Download figureDownload PowerPointFigure. Potential pathways for Ang II–induced inhibition of PPAR-γ transrepression activity are depicted. After PPAR-γ ligand binding, an adjunct is formed with small ubiquitin-like modifier 1 (SUMO1) on lysine 365 of PPAR-γ (Su-PPAR-γ) via the action of E2 ligase Ubc9 and E3 ligase PIAS1. Sumoylation and/or binding to the corepressor (NCoR)/histone deacetylase 3 (HDAC3) complex may be abrogated if PPAR-γ is phosphorylated as a result of Ang II–induced activation of Bcr kinase. Alternatively, dissociation of NCoR from the NCoR/HDAC3 complex may be accelerated, leading to degradation in the 19S proteasome. These mechanisms lead to abrogation of transrepression of inflammatory mediators. Other potential mechanisms include inhibition of the effect of PPAR-γ on C/EBP-δ that induces expression of inflammatory cytokines.How does the interaction of Ang II and PPAR-γ signaling occur? In this issue of Circulation Research, Alexis et al16 provide evidence of a role of Bcr kinase in the crosstalk between Ang II and PPAR-γ. These authors investigated the role of Bcr, which is a serine/threonine kinase expressed in many cell types and activated by PDGF, highly expressed in neointima after vascular injury. This kinase was described as the breakpoint of the Philadelphia chromosome translocation, which is found in chronic myelogenous leukemia. The study of Alexis et al demonstrated that Bcr kinase was stimulated by Ang II, its overexpression abrogated PPAR-γ activity, and its downregulation resulted in recovery of PPAR-γ activity. Bcr exerted its effects via serine 82 phosphorylation of PPAR-γ. Silencing of Bcr abrogated Ang II–induced NF-κB upregulation, and dominant negative PPAR-γ reversed dominant negative Bcr–induced inhibition of NF-κB, indicating that Bcr was upstream of PPAR-γ. Furthermore, Alexis et al were able to demonstrate in vivo that intimal proliferation in low-flow carotid arteries was decreased by gene inactivation of Bcr in mice, which indicates that Bcr kinase has an important role in growth of VSMCs in vivo. This occurred, in part, via effects of Bcr kinase on PPAR-γ/NF-κB transcriptional activity.The study of Alexis et al16 has some limitations. Although it establishes quite unambiguously a role for Bcr kinase, it does not illuminate the mechanism by which Ang II–induced PPAR-γ phosphorylation via Bcr affects transrepression mechanisms and interferes with the ability of PPAR-γ to exert its antiinflammatory or growth-inhibitory actions (Figure). Does serine 82 phosphorylation of PPAR-γ affect ligand binding, sumoylation of PPAR-γ and release of the corepressor/histone deacetylase 3 complex or the 19S proteasome degradation of the latter, or is it the effect on C/EBP-β or C/EBP-δ that is altered? Because Ang II activates SHIP2, which is inhibited by PPAR-γ,10 are Bcr kinase activation and PPAR-γ phosphorylation blocking this effect, or are they affecting the action of PPAR-γ on activity of the mTOR substrate 4E-BP1, which has been shown to be modulated by Bcr kinase activation17? Thus the article by Alexis et al, although providing novel insights, does not give us a full picture of how the fire that Ang II lights in the vasculature is able to overcome the extinguishing action of PPAR-γ.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingSupported by Canadian Institutes of Health Research grants 37917 and 82790, the Canada Fund for Innovation, and the Canada Research Chairs program of the Government of Canada (all to E.L.S.).DisclosuresNone.FootnotesCorrespondence to Ernesto L. Schiffrin MD, PhD, FRSC, FRCPC, Department of Medicine, SMBD-Jewish General Hospital, #B-127, 3755 Côte-Ste-Catherine Rd, Montreal, Quebec, Canada H3T 1E2. E-mail [email protected] References 1 Diep QN, El Mabrouk M, Cohn JS, Endemann D, Amiri F, Virdis A, Neves MF, Schiffrin EL. Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-γ. Circulation. 2002; 105: 2296–2302.LinkGoogle Scholar2 Iglarz M, Touyz RM, Amiri F, Lavoie MF, Diep QN, Schiffrin EL. Effect of peroxisome proliferator-activated receptor-α and -γ activators on vascular remodeling in endothelin-dependent hypertension. Arterioscler Thromb Vasc Biol. 2003; 23: 45–51.LinkGoogle Scholar3 Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol. 2005; 288: H1037–H1043.CrossrefMedlineGoogle Scholar4 Duan SZ, Usher MG, Mortensen RM. Peroxisome proliferator-activated receptor-mediated effects in the vasculature. Circ Res. 2008; 102: 283–294.LinkGoogle Scholar5 Law RE, Hsueh WA. PPARγ and atherosclerosis: effects on cell growth and movement. Arterioscler Thromb Vasc Biol. 2001; 21: 1891–1895.CrossrefMedlineGoogle Scholar6 Abe M, Hasegawa K, Wada H, Morimoto T, Yanazume T, Kawamura T, Hirai M, Furukawa Y, Kita T. GATA-6 is involved in PPARgamma-mediated activation of differentiated phenotype in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003; 23: 404–410.LinkGoogle Scholar7 Law RE, Goetze S, Xi X-P, Jackson S, Kawano Y, Demer L, Fishbein MC, Meehan WP, Hsueh WA. Expression and function of PPARγ in rat and human vascular smooth muscle cells. Circulation. 2000; 101: 1311–1318.CrossrefMedlineGoogle Scholar8 Wakino S, Kintscher U, Liu Z, Kim S, Yin F, Ohba M, Kuroki T, Schonthal AH, Hsueh WA, Law RE. Peroxisome proliferator-activated receptor gamma ligands inhibit mitogenic induction of p21(Cip1) by modulating the protein kinase Cdelta pathway in vascular smooth muscle cells. J Biol Chem. 2001; 276: 47650–47657.CrossrefMedlineGoogle Scholar9 Bruemmer D, Yin F, Liu J, Berger JP, Kiyono T, Chen J, Fleck E, Van Herle AJ, Forman BM, Law RE. Peroxisome proliferator-activated receptor gamma inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells. Mol Endocrinol. 2003; 17: 1005–1018.CrossrefMedlineGoogle Scholar10 Benkirane K, Amiri F, Diep QN, El Mabrouk M, Schiffrin EL. PPAR-γ inhibits angiotensin II-induced cell growth via SHIP2 and 4E-BP1. Am J Physiol Heart Circ Physiol. 2006; 290: H390–H397.CrossrefMedlineGoogle Scholar11 Bruemmer D, Yin F, Liu J, Berger JP, Sakai T, Blaschke F, Fleck E, Van Herle AJ, Forman BM, Law RE. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells. Circ Res. 2003; 93: e38–e47.LinkGoogle Scholar12 Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, Rose DW, Willson TM, Rosenfeld MG, Glass CK. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005; 437: 759–763.CrossrefMedlineGoogle Scholar13 Takata Y, Kitami Y, Yang ZH, Nakamura M, Okura T, and Hiwada K. Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-δ and peroxisome proliferator-activated receptor-γ. Circ Res. 2002; 91: 427–433.LinkGoogle Scholar14 Wang LH, Yang XY, Zhang X, Farrar WL. Inhibition of adhesive interaction between multiple myeloma, and bone stromal cells by PPAR-γ cross-talk with NF-κB and C/EBPβ. Blood. 2007; 110: 4373–4384.CrossrefMedlineGoogle Scholar15 Ruan H, Pownall HJ, Lodish HF. Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J Biol Chem. 2003; 278: 28181–28192.CrossrefMedlineGoogle Scholar16 Alexis JD, Wang N, Che W, Lerner-Marmarosh N, Sahni A, Korshunov VA, Zou Y, Ding B, Yan C, Berk BC, Abe J-i. Bcr kinase activation by angiotensin II inhibits peroxisome proliferator-activated receptor transcriptional activity in vascular smooth muscle cells. Circ Res. 2009; 104: 69–78.LinkGoogle Scholar17 Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST. Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4e-Bp1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res. 2003; 63: 5716–5722.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Chung S, Kim Y, Yang S, Lee Y and Lee M (2016) Nutrigenomic Functions of PPARs in Obesogenic Environments, PPAR Research, 10.1155/2016/4794576, 2016, (1-17), . January 2, 2009Vol 104, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.108.191155PMID: 19118280 Originally publishedJanuary 2, 2009 KeywordsPDGFnuclear receptorremodeling hypertensioninflammationPDF download Advertisement" @default.
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