Abstract
Peroxisome Proliferator-Activated Receptors (PPARs), members of the steroid hormone nuclear receptor superfamily, act as ligand-activated transcription factors controlling the expression of specific target genes. Known PPAR isoforms include PPAR gamma, important in adipogenesis and lipid metabolism, PPAR alpha, implicated in fatty acid metabolism, and PPAR delta, about which the least is known. Recent work implicates PPAR alpha and gamma in vascular biology and atherosclerosis, and will be reviewed here. Such effects may have clinical implications given PPAR agonists in use as pharmacologic agents (eg, thiazolidinediones as insulin sensitizers [gamma] and fibric acids as lipid lowering agents [alpha]).
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References and Recommended Reading
Kuhn TS: The Structure of Scientific Revolutions. Chicago: University of Chicago Press; 1967.
Fickett JW, Wasserman WW: Discovery and modeling of transcriptional regulatory regions. Curr Opin Biotechnol 2000, 11:19–24.
Yla-Herttuala S, Martin JF: Cardiovascular gene therapy. Lancet 2000, 355:213–222.
Ross R: Atherosclerosis — an inflammatory disease. N Eng J Med 1999, 340:115–126.
Libby P: Molecular bases of the acute coronary syndromes. Circulation 1995, 91:2844–2850.
Davies PF, Polacek DC, Handen JS, et al.: A spatial approach to transcriptional profiling: mechanotransduction and the focal origin of atherosclerosis. Trends Biotechnol 1999, 17:347–351.
Rosenberg RD, Aird WC: Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med 1999, 340:1555–1564.
Sobue K, Hayashi K, Nishida W: Expressional regulation of smooth muscle cell-specific genes in association with phenotypic modulation. Mol Cell Biochem 1999, 190:105–118.
Kim S, Iwao H: Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000, 52:11–34.
Spiegelman BM: PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–514.
Henry RR: Thiazolidinediones. Endocrinol Metab Clin North Am 1997, 26:553–573.
Staels B, Dallongeville J, Auwerx J, et al.: Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998, 98:2088–2093.
de Duve C: The peroxisome in retrospect. Ann N Y Acad Sci 1996, 804:1–10.
Willson TM, Brown PJ, Sternbach DD, Henke BR: The PPARs: from orphan receptors to drug discovery. J Med Chem 2000, 43:527–550.
Cattley RC, DeLuca J, Elcombe C, et al.: Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol 1998, 27:47–60.
Mangelsdorf D, Thummel C, Beato M, et al.: The nuclear receptor superfamily: the second decade. Cell 1995, 83:835–839.
Latruffe N, Vamecq J: Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism. Biochimie 1997, 79:81–94.
Chen JD: Steroid/nuclear receptor coactivators. Vitam Horm 2000, 58:391–448.
Tontonoz P, Graves RA, Budavari AI, et al.: Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. Nucleic Acids Res 1994, 22:5628–5634.
Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA: Peroxisome proliferator-activated receptor (PPAR) gamma: adipose- predominant expression and induction early in adipocyte differentiation. Endocrinology 1994, 135:798–800.
Lowell BB: PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999, 99:239–242.
Tontonoz P, Hu E, Spiegelman BM: Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid- activated transcription factor [published erratum appears in Cell 1995 Mar 24;80(6):957]. Cell 1994;79:1147–1156.
Lehmann JM, Moore LB, Smith-Oliver TA, et al.: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995, 270:12953–12956.
Willson TM, Lehmann JM, Kliewer SA: Discovery of ligands for the nuclear peroxisome proliferator-activated receptors. Ann N Y Acad Sci 1996, 804:276–283.
Saltiel AR, Olefsky JM: Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996, 45:1661–1669.
Mahler RJ, Adler ML: Clinical review 102: Type 2 diabetes mellitus: update on diagnosis, pathophysiology, and treatment. J Clin Endocrinol Metab 1999, 84:1165–1171.
Kliewer SA, Lenhard JM, Willson TM, et al.: A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995, 83:813–819.
Forman BM, Tontonoz P, Chen J, et al.: 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995, 83:803–812.
Kliewer SA, Sundseth SS, Jones SA, et al.: Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A 1997, 94:4318–4323.
Tontonoz P, Nagy L, Alvarez JG, et al.: PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998, 93:241–252.
Rossi A, Kapahi P, Natoli G, et al.: Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 2000, 403:103–108.
Reaven GM: Pathophysiology of insulin resistance in human disease. Physiol Rev 1995, 75:473–486.
Haffner SM, Miettinen H: Insulin resistance implications for type II diabetes mellitus and coronary heart disease. Am J Med 1997, 103:152–162.
Laakso M: Insulin resistance and coronary heart disease. Curr Opin Lipidol 1996, 7:217–226.
Plutzky J: Atherosclerotic plaque rupture: emerging insights and opportunities. Am J Cardiol 1999, 84:15J-20J.
Ristow M, Muller-Wieland D, Pfeiffer A, et al.: Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med 1998, 339:953–959.
Vidal-Puig AJ, Considine RV, Jimenez-Linan M, et al.: Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 1997, 99:2416–2422.
Barroso I, Gurnell M, Crowley VE, et al.: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension [Comments]. Nature 1999, 402:880–883.
Rosen ED, Sarraf P, Troy AE, et al.: PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999, 4:611–617.
Barak Y, Nelson MC, Ong ES, et al.: PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999, 4:585–595.
Kubota N, Terauchi Y, Miki H, Tamemoto H, et al.: PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999, 4:597–609.
Miles PD, Barak Y, He W, et al.: Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 2000, 105:287–292.
Greene M, Blumberg B, McBride O, et al.: Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoetic cells and chromosomal mapping. Gene Expr 1995, 4:281–299.
Ricote M, Li AC, Willson TM, et al.: The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998, 391:79–82.
Jiang C, Ting AT, Seed B: PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998, 391:82–86.
Marx N, Sukhova G, Murphy C, et al.: Macrophages in human atheroma contain PPARgamma: differentiation- dependent peroxisomal proliferator-activated receptor gamma (PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol 1998, 153:17–23.
Ricote M, Huang JT, Welch JS, Glass CK: The peroxisome proliferator-activated receptor (PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol 1999, 66:733–739.
Dollery C, McEwan J, Henney A: Matrix metalloproteinases and cardiovascular disease. Circ Res 1995, 77:863–868.
Galis Z, Sukhova G, Lark M, Libby P: Increased expression of matrix metalloproteinases and matrix degradation activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994, 94:2493–2503.
Knox JB, Sukhova GK, Whittemore AD, Libby P: Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation 1997, 95:205–212.
Marx N, Schonbeck U, Lazar MA, et al.: Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 1998, 83:1097–1103.
Goetze S, Xi XP, Kawano H, et al.: PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. J Cardiovasc Pharmacol 1999, 33:798–806.
Law RE, Goetze S, Xi XP, et al.: Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation. 2000, 101:1311–1318.
Staels B, Koenig W, Habib A, et al.: Activation of human aortic smooth muscle cells is inhibited by PPARa but not by PPARg activators. Nature 1998, 393:790–793.
Iijima K, Yoshizumi M, Ako J, et al.: Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in rat aortic smooth muscle cells [published erratum appears in Biochem Biophys Res Commun 1999 Feb 16;255(2):549]. Biochem Biophys Res Commun 1998, 247:353–356.
Couturier C, Brouillet A, Couriaud C, et al.: Interleukin 1beta induces type II-secreted phospholipase A(2) gene in vascular smooth muscle cells by a nuclear factor kappaB and peroxisome proliferator-activated receptor-mediated process. J Biol Chem 1999, 274:23085–23093.
Hattori Y, Hattori S, Kasai K: Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells. Hypertension 1999, 33:943–948.
Benson S, Wu J, Padmanabhan S, Kurtz TW, Pershadsingh HA: Peroxisome proliferator-activated receptor (PPAR)-gamma expression in human vascular smooth muscle cells: inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-gamma activator troglitazone. Am J Hypertens 2000, 13:74–82.
Nagy L, Tontonoz P, Alvarez JG, et al.: Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998, 93:229–240.
Huang JT, Welch JS, Ricote M, et al.: Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 1999, 400:378–382.
Han J, Hajjar DP, Tauras JM, et al.: Nicholson AC. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen- activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma. J Biol Chem 2000, 275:1241–1246.
Spiegelman BM: PPARgamma in monocytes: less pain, any gain? Cell 1998, 93:153–155.
Marx N, Bourcier T, Sukhova GK, et al.: PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol 1999, 19:546–551.
Xin X, Yang S, Kowalski J, Gerritsen ME: Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 1999, 274:9116–9121.
Kato K, Satoh H, Endo Y, et al.: Thiazolidinediones downregulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: A possible role for PPARgamma in endothelial function. Biochem Biophys Res Commun 1999, 258:431–435.
Bishop-Bailey D, Hla T: Endothelial cell apoptosis induced by the peroxisome proliferator- activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2. J Biol Chem 1999, 274:17042–17048.
Satoh H, Tsukamoto K, Hashimoto Y, et al.: Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARgamma on vascular endothelial function. Biochem Biophys Res Commun 1999, 254:757–763.
Schmitz G, Aslanidis C, Lackner KJ: Transcription-modulating drugs: a new frontier in the treatment of essential hypertension. Hypertension 1998, 32:380–386.
Marx N, Mach F, Sauty A, et al.: PPARg activators inhibit IFNg-induced expression of Mig, IP-10, and ITAC, but not MCP-1. J Immunology 2000, in press.
Luster AD: Chemokines: chemotactic cytokines that mediate inflammation. N Engl J Med 1998, 338:436–445.
Su CG, Wen X, Bailey ST, et al.: A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest 1999, 104:383–389.
Minamikawa J, Tanaka S, Yamauchi M, et al.: Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998, 83:1818–1820.
Wolffenbuttel BH, Gomis R, Squatrito S, et al.: Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabet Med 2000, 17:40–47.
Meirhaeghe A, Fajas L, Helbecque N, et al.: A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans. Hum Mol Genet 1998, 7:435–440.
Freake HC: A genetic mutation in PPAR gamma is associated with enhanced fat cell differentiation: implications for human obesity. Nutr Rev 1999, 57:154–156.
Wang XL, Oosterhof J, Duarte N: Peroxisome proliferator-activated receptor gamma C161→T polymorphism and coronary artery disease. Cardiovasc Res 1999, 44:588–594.
Valve R, Sivenius K, Miettinen R, et al.: Two polymorphisms in the peroxisome proliferator-activated receptor- gamma gene are associated with severe overweight among obese women. J Clin Endocrinol Metab 1999, 84:3708–3712.
Knoblauch H, Busjahn A, Muller-Myhsok B, et al.: Peroxisome proliferator-activated receptor gamma gene locus is related to body mass index and lipid values in healthy nonobese subjects. Arterioscler Thromb Vasc Biol 1999, 19:2940–2944.
Issemann I, Green S: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators [Comments]. Nature 1990, 347:645–650.
Fruchart JC, Duriez P, Staels B: Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin Lipidol 1999, 10:245–257.
Tugwood JD, Issemann I, Anderson RG, et al.: The mouse peroxisome proliferator activated receptor recognizes a response element in the 5′ flanking sequence of the rat acyl CoA oxidase gene. EMBO J 1992, 11:433–439.
Schoonjans K, Watanabe M, Suzuki H, et al.: Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem 1995, 270:19269–19276.
Gulick T, Cresci S, Caira T, et al.: The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A 1994, 91:11012–11016.
Rodriguez JC, Gil-Gomez G, Hegardt FG, Haro D: Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem 1994, 269:18767–18772.
Vu-Dac N, Schoonjans K, Kosykh V, et al.: Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest 1995, 96:741–750.
Berthou L, Saladin R, Yaqoob P, et al.: Regulation of rat liver apolipoprotein A-I, apolipoprotein A-II and acyl-coenzyme A oxidase gene expression by fibrates and dietary fatty acids. Eur J Biochem 1995, 232:179–187.
Staels B, Vu Dac N, Kosykh VA, et al.: Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates. J Clin Invest 1995, 95:705–712.
Muerhoff AS, Griffin KJ, Johnson EF: The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid. J Biol Chem 1992, 267:19051–19053.
Lee SS, Pineau T, Drago J, et al.: Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 1995, 15:3012–3022.
Peters JM, Hennuyer N, Staels B, et al.: Alterations in lipoprotein metabolism in peroxisome proliferator- activated receptor alpha-deficient mice. J Biol Chem 1997, 272:27307–27312.
Gearing KL, Gottlicher M, Widmark E, et al.: Fatty acid activation of the peroxisome proliferator activated receptor, a member of the nuclear receptor gene superfamily. J Nutr 1994, 124:1284S-1288S.
Gottlicher M, Widmark E, Li Q, Gustafsson JA: Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci USA 1992, 89:4653–4657.
Vu-Dac N, Schoonjans K, Laine B, et al.: Negative regulation of the human apolipoprotein A-I promoter by fibrates can be attenuated by the interaction of the peroxisome proliferator-activated receptor with its response element. J Biol Chem 1994, 269:31,012–31,018.
Chinetti G, Griglio S, Antonucci M, et al.: Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 1998, 273:25,573–25,580.
Marx N, Sukhova GK, Collins T, et al.: PPAR-alpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 1999, 99:3125–3131.
Jackson SM, Parhami F, Xi XP, Berliner Ja, et al.: Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vasc Biol 1999, 19:2094–2104.
Chen NG, Sarabia SF, Malloy PJ, et al.: PPARgamma agonists enhance human vascular endothelial adhesiveness by increasing ICAM-1 expression. Biochem Biophys Res Commun 1999, 263:718–722.
Pasceri V, Wu HD, Willerson JT, Yeh ET: Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation 2000, 101:235–238.
Frick MH, Elo O, Haapa K, et al.: Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987, 317:1237–1245.
Frick MH, Syvanne M, Nieminen MS, et al.: Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol: Lopid Coronary Angiography Trial (LOCAT) Study Group [Comments]. Circulation 1997, 96:2137–2143.
Ericsson CG, Nilsson J, Grip L, et al.: Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing: the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). Am J Cardiol 1997, 80:1125–1129.
Rubins HB, Robins SJ, Collins D, et al.: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999, 341:410–418.
Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 97:1129–1135.
Delerive PF, Martin-Nizard G, Chinetti F, et al.: 1999. Peroxisome proliferator-activated receptor activators inhibit thrombin- induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 1999, 85(5):394–402.
Sartippour MR, G. Renier: Differential regulation of macrophage peroxisome proliferator-activated receptor expression by glucose role of peroxisome proliferator- activated receptors in lipoprotein lipase gene expression. Arterioscler Thromb Vasc Biol 2000, 1:104–110.
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Plutzky, J. Peroxisome proliferator-activated receptors in vascular biology and atherosclerosis: Emerging insights for evolving paradigms. Curr Atheroscler Rep 2, 327–335 (2000). https://doi.org/10.1007/s11883-000-0067-3
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DOI: https://doi.org/10.1007/s11883-000-0067-3