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PMID: 10696077 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Peroxisome proliferator-activated receptors in the cardiovascular system.

British journal of pharmacology ·Vol. 129 ·No. 5 ·2000-03-00 ·Pages 823-34

Bishop-Bailey D

Abstract

Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARalpha, -delta, and -gamma, which are members of the steriod receptor superfamily. The first member of the family (PPARalpha) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARalpha being involved in beta-oxidation pathways, and PPARgamma in the differentiation of adipocytes. Little is known about the functions of PPARdelta, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands.

MeSH Terms
Animals Cardiovascular Diseases/physiopathology Cardiovascular Physiological Phenomena Humans Receptors, Cytoplasmic and Nuclear/physiology Receptors, Retinoic Acid/physiology Retinoid X Receptors Transcription Factors/physiology
Chemicals
Receptors, Cytoplasmic and Nuclear Receptors, Retinoic Acid Retinoid X Receptors Transcription Factors
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Bishop-Bailey D
Vascular Biology Center, Department of Physiology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut, CT 06030-3505, USA. [email protected]
References (102)
102 references, click to expand
  1. 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 Sep 3;85(5):394-402 PMID: 10473669
  2. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses.
    J Immunol. 2000 Feb 1;164(3):1364-71 PMID: 10640751
  3. Bimodal distribution of the prostaglandin I2 synthase antigen in smooth muscle cells.
    J Biol Chem. 1983 May 10;258(9):5922-6 PMID: 6406508
  4. Nuclear receptor that identifies a novel retinoic acid response pathway.
    Nature. 1990 May 17;345(6272):224-9 PMID: 2159111
  5. Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions.
    Proc Natl Acad Sci U S A. 1990 Sep;87(18):6959-63 PMID: 1698286
  6. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.
    Nature. 1990 Oct 18;347(6294):645-50 PMID: 2129546
  7. Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.
    J Clin Invest. 1991 Apr;87(4):1146-52 PMID: 2010531
  8. Prostaglandin and thromboxane biosynthesis.
    Pharmacol Ther. 1991;49(3):153-79 PMID: 1905023
  9. Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor gamma.
    J Biol Chem. 1998 Jan 23;273(4):1855-8 PMID: 9442016
  10. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand.
    Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4333-7 PMID: 9539737
  11. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.
    Diabetes. 1998 Apr;47(4):507-14 PMID: 9568680
  12. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma.
    Cell. 1998 Apr 17;93(2):229-40 PMID: 9568715
  13. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL.
    Cell. 1998 Apr 17;93(2):241-52 PMID: 9568716
  14. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312-7 PMID: 9113986
  15. 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 Apr 29;94(9):4318-23 PMID: 9113987
  16. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients.
    Diabetes. 1997 Aug;46(8):1319-27 PMID: 9231657
  17. Low density lipoprotein oxidation and its pathobiological significance.
    J Biol Chem. 1997 Aug 22;272(34):20963-6 PMID: 9261091
  18. Tumorigenic transformation of immortalized ECV endothelial cells by cyclooxygenase-1 overexpression.
    J Biol Chem. 1997 Aug 22;272(34):21455-60 PMID: 9261162
  19. Isolation and characterization of PBP, a protein that interacts with peroxisome proliferator-activated receptor.
    J Biol Chem. 1997 Oct 10;272(41):25500-6 PMID: 9325263
  20. Induction of cyclooxygenase-2 in human saphenous vein and internal mammary artery.
    Arterioscler Thromb Vasc Biol. 1997 Sep;17(9):1644-8 PMID: 9327757
  21. Is there a role for 15-lipoxygenase in atherogenesis?
    Biochem Pharmacol. 1997 Nov 1;54(9):953-9 PMID: 9374414
  22. The endothelium in coronary artery disease.
    Cardiology. 1997;88 Suppl 3:3-19 PMID: 9397288
  23. Expression of lipocalin-type prostaglandin D synthase (beta-trace) in human heart and its accumulation in the coronary circulation of angina patients.
    Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14689-94 PMID: 9405674
  24. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation.
    Nature. 1998 Jan 1;391(6662):79-82 PMID: 9422508
  25. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.
    Nature. 1998 Jan 1;391(6662):82-6 PMID: 9422509
  26. The adipocyte and hemostatic balance in obesity: studies of PAI-1.
    Arterioscler Thromb Vasc Biol. 1998 Jan;18(1):1-6 PMID: 9445248
  27. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein.
    Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7614-9 PMID: 9636198
  28. Co-activators and co-repressors in the integration of transcriptional responses.
    Curr Opin Cell Biol. 1998 Jun;10(3):373-83 PMID: 9640539
  29. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators.
    Nature. 1998 Jun 25;393(6687):790-3 PMID: 9655393
  30. Terminal differentiation of human breast cancer through PPAR gamma.
    Mol Cell. 1998 Feb;1(3):465-70 PMID: 9660931
  31. 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 Jul;153(1):17-23 PMID: 9665460
  32. Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo.
    Cancer Res. 1998 Aug 1;58(15):3344-52 PMID: 9699665
  33. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha.
    J Biol Chem. 1998 Sep 11;273(37):23786-92 PMID: 9726988
  34. Differentiation and reversal of malignant changes in colon cancer through PPARgamma.
    Nat Med. 1998 Sep;4(9):1046-52 PMID: 9734398
  35. A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator- activated receptor alpha- deficient mice.
    J Clin Invest. 1998 Sep 15;102(6):1083-91 PMID: 9739042
  36. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.
    Nature. 1998 Sep 10;395(6698):137-43 PMID: 9744270
  37. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation.
    N Engl J Med. 1998 Oct 1;339(14):953-9 PMID: 9753710
  38. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages.
    J Biol Chem. 1998 Oct 2;273(40):25573-80 PMID: 9748221
  39. Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells.
    Biochem Biophys Res Commun. 1998 May 19;246(2):370-4 PMID: 9610365
  40. Cyclooxygenase regulates angiogenesis induced by colon cancer cells.
    Cell. 1998 May 29;93(5):705-16 PMID: 9630216
  41. 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 Feb;11(2):433-9 PMID: 1537328
  42. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors.
    Cell. 1992 Mar 6;68(5):879-87 PMID: 1312391
  43. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.
    Genes Dev. 1992 Mar;6(3):329-44 PMID: 1312497
  44. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor.
    Proc Natl Acad Sci U S A. 1992 May 15;89(10):4653-7 PMID: 1316614
  45. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase.
    Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4888-92 PMID: 1594589
  46. Human cyclooxygenase-2 cDNA.
    Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384-8 PMID: 1380156
  47. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors.
    Nature. 1992 Aug 27;358(6389):771-4 PMID: 1324435
  48. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids.
    Mol Endocrinol. 1992 Oct;6(10):1634-41 PMID: 1333051
  49. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor.
    Biochemistry. 1993 Jun 1;32(21):5598-604 PMID: 7684926
  50. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver.
    J Biol Chem. 1993 Dec 25;268(36):26817-20 PMID: 8262913
  51. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693-7 PMID: 8265610
  52. Oxidation, lipoxygenase, and atherogenesis.
    Ann N Y Acad Sci. 1994 Apr 18;714:211-24 PMID: 8017770
  53. Effects of pioglitazone on calcium channels in vascular smooth muscle.
    Hypertension. 1994 Aug;24(2):170-5 PMID: 8039840
  54. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.
    Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355-9 PMID: 8041794
  55. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers.
    Endocr Rev. 1994 Jun;15(3):391-407 PMID: 8076589
  56. The human peroxisome proliferator-activated receptor (PPAR) subtype NUC1 represses the activation of hPPAR alpha and thyroid hormone receptors.
    J Biol Chem. 1995 Feb 24;270(8):3836-40 PMID: 7876127
  57. Enhanced levels of lipoperoxides in low density lipoprotein incubated with murine fibroblast expressing high levels of human 15-lipoxygenase.
    J Biol Chem. 1995 Mar 10;270(10):5191-7 PMID: 7890629
  58. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping.
    Gene Expr. 1995;4(4-5):281-99 PMID: 7787419
  59. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells.
    J Med Chem. 1995 Aug 4;38(16):3146-55 PMID: 7636877
  60. Differential activation of peroxisome proliferator-activated receptors by eicosanoids.
    J Biol Chem. 1995 Oct 13;270(41):23975-83 PMID: 7592593
  61. Angiogenesis in cancer, vascular, rheumatoid and other disease.
    Nat Med. 1995 Jan;1(1):27-31 PMID: 7584949
  62. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.
    Cell. 1995 Dec 1;83(5):803-12 PMID: 8521497
  63. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation.
    Cell. 1995 Dec 1;83(5):813-9 PMID: 8521498
  64. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.
    Endocrinology. 1996 Jan;137(1):354-66 PMID: 8536636
  65. The RXR heterodimers and orphan receptors.
    Cell. 1995 Dec 15;83(6):841-50 PMID: 8521508
  66. Differential activation of adipogenesis by multiple PPAR isoforms.
    Genes Dev. 1996 Apr 15;10(8):974-84 PMID: 8608944
  67. The role of oxidized lipoproteins in atherogenesis.
    Free Radic Biol Med. 1996;20(5):707-27 PMID: 8721615
  68. A decade of molecular biology of retinoic acid receptors.
    FASEB J. 1996 Jul;10(9):940-54 PMID: 8801176
  69. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia.
    J Clin Invest. 1996 Oct 15;98(8):1897-905 PMID: 8878442
  70. Lipoxygenase activity in heart cells.
    FEBS Lett. 1996 Oct 21;395(2-3):148-52 PMID: 8898083
  71. Adipogenesis and obesity: rounding out the big picture.
    Cell. 1996 Nov 1;87(3):377-89 PMID: 8898192
  72. The PPARalpha-leukotriene B4 pathway to inflammation control.
    Nature. 1996 Nov 7;384(6604):39-43 PMID: 8900274
  73. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice.
    Biochim Biophys Acta. 1996 Nov 11;1304(1):65-84 PMID: 8944751
  74. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs.
    J Biol Chem. 1997 Feb 7;272(6):3406-10 PMID: 9013583
  75. Cloning and identification of mouse steroid receptor coactivator-1 (mSRC-1), as a coactivator of peroxisome proliferator-activated receptor gamma.
    Gene Expr. 1996;6(3):185-95 PMID: 9041124
  76. Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists.
    J Biol Chem. 1997 Mar 21;272(12):8071-6 PMID: 9065481
  77. Troglitazone reduces contraction by inhibition of vascular smooth muscle cell Ca2+ currents and not endothelial nitric oxide production.
    Diabetes. 1997 Apr;46(4):659-64 PMID: 9075808
  78. Estrogen-induced production of a peroxisome proliferator-activated receptor (PPAR) ligand in a PPARgamma-expressing tissue.
    J Biol Chem. 1998 Nov 13;273(46):30131-8 PMID: 9804768
  79. Mechanism of action of fibrates on lipid and lipoprotein metabolism.
    Circulation. 1998 Nov 10;98(19):2088-93 PMID: 9808609
  80. Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma.
    J Biol Chem. 1998 Nov 20;273(47):31108-12 PMID: 9813012
  81. A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor gamma-activating properties.
    J Biol Chem. 1998 Dec 4;273(49):32679-84 PMID: 9830009
  82. Co-regulation of tissue-specific alternative human carnitine palmitoyltransferase Ibeta gene promoters by fatty acid enzyme substrate.
    J Biol Chem. 1998 Dec 4;273(49):32901-9 PMID: 9830040
  83. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells.
    Circ Res. 1998 Nov 30;83(11):1097-103 PMID: 9831704
  84. Cyclo-oxygenase-2 in vascular smooth muscle.
    Int J Mol Med. 1999 Jan;3(1):41-8 PMID: 9864384
  85. Atherosclerosis--an inflammatory disease.
    N Engl J Med. 1999 Jan 14;340(2):115-26 PMID: 9887164
  86. 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 Jan 27;254(3):757-63 PMID: 9920814
  87. The relationship of hydroxyeicosatetraenoic acids and F2-isoprostanes to plaque instability in human carotid atherosclerosis.
    J Clin Invest. 1999 Feb;103(3):421-7 PMID: 9927504
  88. Endothelial dysfunction in human disease.
    J Mol Cell Cardiol. 1999 Jan;31(1):51-60 PMID: 10072715
  89. Differential induction of cyclooxygenase-2 in human arterial and venous smooth muscle: role of endogenous prostanoids.
    Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1655-61 PMID: 9763540
  90. Activation of PPARgamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells.
    Gastroenterology. 1998 Nov;115(5):1049-55 PMID: 9797355
  91. 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 Mar;19(3):546-51 PMID: 10073956
  92. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages.
    Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):646-55 PMID: 10073969
  93. Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo.
    J Biol Chem. 1999 Mar 26;274(13):9116-21 PMID: 10085162
  94. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3951-6 PMID: 10097144
  95. Global transcription regulators of eukaryotes.
    Cell. 1999 Mar 19;96(6):759-67 PMID: 10102264
  96. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors.
    Mol Cell. 1999 Mar;3(3):397-403 PMID: 10198642
  97. A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.
    Proc Natl Acad Sci U S A. 1999 May 25;96(11):6102-6 PMID: 10339548
  98. Fibrous cap formation or destruction--the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation.
    Cardiovasc Res. 1999 Feb;41(2):345-60 PMID: 10341834
  99. Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2.
    J Biol Chem. 1999 Jun 11;274(24):17042-8 PMID: 10358055
  100. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice.
    J Clin Invest. 1999 Jun;103(11):1597-604 PMID: 10359569
  101. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.
    Circulation. 1999 Jun 22;99(24):3125-31 PMID: 10377075
  102. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase.
    Nature. 1999 Jul 22;400(6742):378-82 PMID: 10432118
Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0703149
Email
[email protected]
Published
2000-03-00
Pages
823-34
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1571927
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.bjp.0703149 PMC Full Text View journal details
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