Direct antiatherosclerotic effects of PPAR agonists

Current Opinion in Lipidology

Volumn 20, Issue 1, 2009, Pages 24-29

  Jandeleit Dahm, Karin A M ^a   Calkin, Anna ^a   Tikellis, Chris ^a   Thomas, Merlin ^a  

^a BAKER IDI HEART AND DIABETES INSTITUTE   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; [4 [2 (3 FLUORO 4 TRIFLUOROMETHYLPHENYL) 4 METHYL 5 THIAZOLYLMETHYLTHIO] 2 METHYLPHENOXY]ACETIC ACID; ANGIOTENSIN RECEPTOR ANTAGONIST; BEZAFIBRATE; FENOFIBRATE; FIBRIC ACID DERIVATIVE; GEMFIBROZIL; GW 625019; GW 766954; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MURAGLITAZAR; NETOGLITAZONE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIOGLITAZONE; PLX 204; ROSIGLITAZONE; TELMISARTAN; TESAGLITAZAR; UNCLASSIFIED DRUG;

ATHEROSCLEROTIC CARDIOVASCULAR DISEASE; ATHEROSCLEROTIC PLAQUE; CARDIOVASCULAR RISK; CLINICAL TRIAL; CORONARY ARTERY ATHEROSCLEROSIS; CORONARY RISK; CREATININE BLOOD LEVEL; DIABETES MELLITUS; DISEASE COURSE; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG WITHDRAWAL; FLUID RETENTION; GLOMERULUS FILTRATION RATE; HEART INFARCTION; HEART STRESS; HUMAN; IMMUNE RESPONSE; INFLAMMATION; ISCHEMIC HEART DISEASE; METABOLIC DISORDER; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; STREPTOZOCIN DIABETES; TRANSACTIVATION;

ANIMALS; ARTERIES; ATHEROSCLEROSIS; HUMANS; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; PHARMACOLOGICAL PROCESSES; PROTEIN ISOFORMS;

EID: 58849141318     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/MOL.0b013e32831f1b18     Document Type: Review

References (71)

1. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47:507-514.
2. 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.
3. Inoue I, Shino K, Noji S, et al. Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. Biochem Biophys Res Commun 1998; 246:370-374.
4. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 1998; 393:790-793.
5. 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; 273:25573-25580.
6. Chinetti G, Gbaguidi FG, Griglio S, et al. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 2000; 101:2411-2417.
7. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98:2088-2093.
8. Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 1993; 94:350-356.
9. Duez H, Chao YS, Hernandez M, et al. Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. J Biol Chem 2002; 277:48051-48057.
10. Calkin AC, Cooper ME, Jandeleit-Dahm KA, Allen TJ. Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation. Diabetologia 2006; 49:766-774.
11. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001; 357:905-910.
12. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002; 162:2597-2604.
13. Koskinen P, Manttari M, Manninen V, et al. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992; 15:820-825.
14. Keech A, Simes PJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366:1849-1861.
15. Inoue I, Goto S, Matsunaga T, et al. The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+, Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 2001; 50:3-11.
16. Inoue H, Tanabe T, Umesono K. Feedback control of cyclooxygenase-2 expression through PPARgamma. J Biol Chem 2000; 275: 28028-28032.
17. Calkin AC, Forbes JM, Smith CM, et al. Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arterioscler Thromb Vasc Biol 2005; 25:1903-1909.
18. Marx N. PPARgamma and vascular inflammation: adding another piece to the puzzle. Circ Res 2002; 91:373-374.
19. Jackson SM, Parhami F, Xi XP, 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.
20. Marx N, Mackman N, Schonbeck U, et al. PPARalpha activators inhibit tissue factor expression and activity in human monocytes. Circulation 2001; 103:213-219.
21. Harja E, Bu DX, Hudson Bl, et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice. J Clin Invest 2008; 118:183-194.
22. Soro-Paavonen A, Watson AM, Li J, et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 2008; 57:2461 -2469.
23. Delerive P, Martin-Nizard F, Chinetti G, et al. 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; 85:394-402.
24. Al-Khalili L, Forsgren M, Kannisto K, et al. Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1. Diabetologia 2005; 48:1173-1179.
25. Bell DS. Beta-cell rejuvenation with thiazolidinediones. Am J Med 2003; 115 (Suppl 8A):20S-23S.
26. Tikellis C, Wookey PJ, Candido R, et al. Improved islet morphology after blockade of the renin- angiotensin system in the ZDF rat. Diabetes 2004; 53:989-997.
27. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351:1106-1118.
28. Collins AR, Meehan WP, Kintscher U, et al. Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21:365-371.
29. Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000; 106:523-531.
30. Chen Z, Ishibashi S, Perrey S, et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 2001; 21:372-377.
31. Marx N, Walcher D, Ivanova N, et al. Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products. Diabetes 2004; 53:2662-2668.
32. Touyz RM, Schiffrin EL. Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications. Vascul Pharmacol 2006; 45:19-28.
33. Calnek DS, Mazzella L, Roser S, et al. Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 2003; 23:52-57.
34. Matsumoto T, Kobayashi T, Kamata K. Relationships among ET-1, PPARgamma, oxidative stress and endothelial dysfunction in diabetic animals. J Smooth Muscle Res 2008; 44:41-55. An article emphasizing the relationship between PPARγ, the endothelin system and oxidative stress.
35. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366:1279-1289.
36. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457-2471. A controversial meta-analysis of studies using rosiglitazone and risk of cardiovascular events.
37. Tontonoz P, Nagy L, Alvarez JG, et al. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998; 93:241 - 252.
38. Nagy L, Tontonoz P, Alvarez JG, et al. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998; 93:229-240.
39. Chinetti G, Lestavel S, Bocher V, et al. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 2001; 7:53-58.
40. Chawla A, Barak Y, Nagy L, et al. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001; 7:48-52.
41. Chawla A, Boisvert WA, Lee CH, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 2001; 7:161-171.
42. 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.
43. Mallat Z, Besnard S, Duriez M, et al. Protective role of interleukin-10 in atherosclerosis. Circ Res 1999; 85:e17-e24.
44. Thompson PW, Bayliffe Al, Warren AP, Lamb JR. lnterleukin-10 is upregulated by nanomolar rosiglitazone treatment of mature dendritic cells and human CD4+ T cells. Cytokine 2007; 39:184-191. A study showing that antioxidant defence mechanisms can be upregulated by PPARγ agonists.
45. Kwak BR, Myit S, Mulhaupt F, et al. PPARgamma but not PPARalpha ligands are potent repressors of major histocompatibility complex class II induction in atheroma-associated cells. Circ Res 2002; 90:356-362.
46. Takeda K, Ichiki T, Tokunou T, et al. Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells. Circulation 2000; 102:1834-1839.
47. Tao L, Liu HR, Gao E, et al. Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia. Circulation 2003; 108:2805-2811.
48. Candido R, Allen TJ, Lassila M, et al. Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis. Circulation 2004; 109:1536-1542.
49. Kurtz TW, Pravenec M. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. J Hypertens 2004; 22:2253-2261.
50. Bagi Z, Koller A, Kaley G. PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Am J Physiol Heart Circ Physiol 2004; 286:H742-H748.
51. Shi Y, Hon M, Evans RM. The peroxisome proliferator-activated receptor delta, an integrator of transcriptional repression and nuclear receptor signaling. Proc Natl Acad Sci U S A 2002; 99:2613-2618.
52. Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008; 134:405-415. A recent study demonstrating a novel metabolic action of PPARδ in skeletal muscle altering metabolic gene expression as seen in exercise.
53. Sprecher DL, Massien C, Pearce G, et al. Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Arterioscler Thromb Vasc Biol 2007; 27:359-365.
54. Graham TL, Mookherjee C, Suckling KE, et al. The PPARdelta agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice. Atherosclerosis 2005; 181:29-37.
55. Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 2004; 114:1564-1576.
56. Lee CH, Chawla A, Urbiztondo N, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science 2003; 302:453-457.
57. Barish GD, Atkins AR, Downes M, et al. PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis. Proc Natl Acad Sci USA 2008; 105:4271-4276. A very important study showing that PPARδ suppresses atherosclerosis by reducing inflammatory pathways.
58. Zhang H, Pi R, Li R, et al. PPARbeta/delta activation inhibits angiotensin II-induced collagen type I expression in rat cardiac fibroblasts. Arch Biochem Biophys 2007; 460:25-32. These results emphasize the counteracting effects of angiotensin II and PPAR-γ agonism, for example, on collagen expression in the cardiac fibroblast.
59. Brunelli L, Cieslik KA, Alcorn JL, et al. Peroxisome proliferator activated receptor-delta upregulates 14-3-3 epsilon in human endothelial cells via CCAAT/enhancer binding protein-beta. Circ Res 2007; 100:e59-e71.
60. Takata Y, Liu J, Yin F, et al. PPARdelta-mediated antiinflammatory mechanisms inhibit angiotensin ll-accelerated atherosclerosis. Proc Natl Acad Sci U S A 2008; 105:4277-4282. A recent demonstration of the antiatherosclerotic effect of PPAR6 and the antagonistic effect to the actions of angiotensin II.
61. Buse JB, Rubin CJ, Frederich R, et al. Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin Ther 2005; 27:1181-1195.
62. Kendall DM, Rubin CJ, Mohideen P, et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study. Diabetes Care 2006; 29:1016-1023.
63. Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 2004; 27:1324-1329.
64. Goldstein BJ, Rosenstock J, Anzalone D, et al. Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12-week dose-ranging trial. Curr Med Res Opin 2006; 22:2575-2590.
65. Zadelaar AS, Boesten LS, Jukema JW, et al. Dual PPARalpha/gamma agonist tesaglitazar reduces atherosclerosis in insulin-resistant and hypercholesterolemicApoE*3Leiden mice. Arterioscler Thromb Vasc Biol 2006; 26:2560-2566.
66. Chira EC, McMillen TS, Wang S, et al. Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice. Atherosclerosis 2007; 195:100-109. An experimental evidence for the antiatherosclerotic effect of a dual PPAR agonist.
67. Calkin AC, Allen TJ, Lassila M, et al. Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse. Atherosclerosis 2007; 195:17-22. This study describes the proatherosclerotic effect of a dual PPAR agonist in an experimental model of the diabetic apoE knockout mouse.
68. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005; 294:2581 -2586.
69. Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care 1998; 21:641-648.
70. Tenenbaum A, Motro M, Fisman EZ. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovasc Diabetol 2005; 4:14.
71. Arcavi L, Behar S, Caspi A, et al. High fasting glucose levels as a predictor of worse clinical outcome in patients with coronary artery disease: results from the Bezafibrate Infarction Prevention (BIP) study. Am Heart J 2004; 147:239-245.