Skip to main content
SpringerLink
Log in

PPAR transcriptional activator complex polymorphisms and the promise of individualized therapy for heart failure

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

The PPAR gene pathway consists of interrelated genes that encode transcription factors, enzymes, and downstream targets which coordinately act to regulate cellular processes central to glucose and lipid metabolism. The pathway includes the PPAR genes themselves, other class II nuclear hormone receptor transcription factors within the PPAR family, PPAR co-activators, PPAR co-repressors, and downstream metabolic gene targets. This review focuses on the transcription factors that comprise the PPAR transcriptional activator complex—the PPARs (PPARα, PPARβ, or PPARγ), PPAR heterodimeric partners, such as RXRα, and PPAR co-activators, such as PPARγ coactivator 1α (PGC-1α) and the estrogen-related receptors (ERRα, ERRβ, and ERRγ). These transcription factors have been implicated in the development of myocardial hypertrophy and dilated cardiomyopathy as well as response to myocardial ischemia/infarction and, by association, ischemic cardiomyopathy. Human expression studies and animal data are presented as the background for a discussion of the emerging field of pharmacogenetics as it applies to these genes and the consequent implications for the individualization of therapy for patients with heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

References

  1. Berkenstam A, Gustafsson JA (2005) Nuclear receptors and their relevance to diseases related to lipid metabolism. Curr Opin Pharmacol 5:171–176. doi:10.1016/j.coph.2005.01.003

    Article  CAS  PubMed  Google Scholar 

  2. Benoit G, Malewicz M, Perlmann T (2004) Digging deep into the pockets of orphan nuclear receptors: insights from structural studies. Trends Cell Biol 14:369–376. doi:10.1016/j.tcb.2004.05.007

    Article  CAS  PubMed  Google Scholar 

  3. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R et al (1998) Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395:137–143. doi:10.1038/25931

    Article  CAS  PubMed  Google Scholar 

  4. Zhu Y, Kan L, Qi C, Kanwar YS, Yeldandi AV, Rao MS et al (2000) Isolation and characterization of peroxisome proliferator-activated receptor (PPAR) interacting protein (PRIP) as a coactivator for PPAR. J Biol Chem 275:13510–13516. doi:10.1074/jbc.275.18.13510

    Article  CAS  PubMed  Google Scholar 

  5. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358:771–774. doi:10.1038/358771a0

    Article  CAS  PubMed  Google Scholar 

  6. Qi C, Zhu Y, Reddy JK (2000) Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys 32(Spring):187–204. doi:10.1385/CBB:32:1-3:187

    Article  CAS  PubMed  Google Scholar 

  7. Spiegelman BM, Puigserver P, Wu Z (2000) Regulation of adipogenesis and energy balance by PPARgamma and PGC-1. Int J Obes Relat Metab Disord 24(Suppl 4):S8–S10

    CAS  PubMed  Google Scholar 

  8. Yu C, Markan K, Temple KA, Deplewski D, Brady MJ, Cohen RN (2005) The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor gamma transcriptional activity and repress 3T3–L1 adipogenesis. J Biol Chem 280:13600–13605. doi:10.1074/jbc.M409468200

    Article  CAS  PubMed  Google Scholar 

  9. Krogsdam AM, Nielsen CA, Neve S, Holst D, Helledie T, Thomsen B et al (2002) Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation. Biochem J 363:157–165. doi:10.1042/0264-6021:3630157

    Article  CAS  PubMed  Google Scholar 

  10. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De oliveira R et al (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429:771–776. doi:10.1038/nature02583

    Article  CAS  PubMed  Google Scholar 

  11. Westin S, Kurokawa R, Nolte RT, Wisely GB, McInerney EM, Rose DW et al (1998) Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Nature 395:199–202. doi:10.1038/26040

    Article  CAS  PubMed  Google Scholar 

  12. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856. doi:10.1172/JCI10268

    Article  CAS  PubMed  Google Scholar 

  13. Huss JM, Kelly DP (2004) Nuclear receptor signaling and cardiac energetics. Circ Res 95:568–578. doi:10.1161/01.RES.0000141774.29937.e3

    Article  CAS  PubMed  Google Scholar 

  14. Horard B, Vanacker JM (2003) Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand. J Mol Endocrinol 31:349–357. doi:10.1677/jme.0.0310349

    Article  CAS  PubMed  Google Scholar 

  15. Huss JM, Kopp RP, Kelly DP (2002) Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 277:40265–40274. doi:10.1074/jbc.M206324200

    Article  CAS  PubMed  Google Scholar 

  16. Schreiber SN, Knutti D, Brogli K, Uhlmann T, Kralli A (2003) The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha). J Biol Chem 278:9013–9018. doi:10.1074/jbc.M212923200

    Article  CAS  PubMed  Google Scholar 

  17. Ichida M, Nemoto S, Finkel T (2002) Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma Coactivator-1 alpha (PGC-1alpha). J Biol Chem 277:50991–50995. doi:10.1074/jbc.M210262200

    Article  CAS  PubMed  Google Scholar 

  18. Huss JM, Torra IP, Staels B, Giguere V, Kelly DP (2004) Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol 24:9079–9091. doi:10.1128/MCB.24.20.9079-9091.2004

    Article  CAS  PubMed  Google Scholar 

  19. Dufour CR, Wilson BJ, Huss JM, Kelly DP, Alaynick WA, Downes M et al (2007) Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERR alpha and gamma. Cell Metab 5:345–356. doi:10.1016/j.cmet.2007.03.007

    Article  CAS  PubMed  Google Scholar 

  20. Dewald O, Sharma S, Adrogue J, Salazar R, Duerr GD, Crapo JD et al (2005) Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity. Circulation 112:407–415. doi:10.1161/CIRCULATIONAHA.105.536318

    Article  CAS  PubMed  Google Scholar 

  21. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP (1996) Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94:2837–2842

    CAS  PubMed  Google Scholar 

  22. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP (2000) Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J Clin Invest 105:1723–1730. doi:10.1172/JCI9056

    Article  CAS  PubMed  Google Scholar 

  23. Cheng L, Ding G, Qin Q, Huang Y, Lewis W, He N et al (2004) Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 10:1245–1250. doi:10.1038/nm1116

    Article  CAS  PubMed  Google Scholar 

  24. Planavila A, Rodriguez-Calvo R, Jove M, Michalik L, Wahli W, Laguna JC et al (2005) Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes. Cardiovasc Res 65:832–841. doi:10.1016/j.cardiores.2004.11.011

    Article  CAS  PubMed  Google Scholar 

  25. Jamshidi Y, Montgomery HE, Hense HW, Myerson SG, Torra IP, Staels B et al (2002) Peroxisome proliferator—activated receptor alpha gene regulates left ventricular growth in response to exercise and hypertension. Circulation 105:950–955. doi:10.1161/hc0802.104535

    Article  CAS  PubMed  Google Scholar 

  26. Sher T, Yi HF, McBride OW, Gonzalez FJ (1993) cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry 32:5598–5604. doi:10.1021/bi00072a015

    Article  CAS  PubMed  Google Scholar 

  27. Schunkert H, Hengstenberg C, Holmer SR, Broeckel U, Luchner A, Muscholl MW et al (1999) Lack of association between a polymorphism of the aldosterone synthase gene and left ventricular structure. Circulation 99:2255–2260

    CAS  PubMed  Google Scholar 

  28. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H (2001) Metabolic gene expression in fetal and failing human heart. Circulation 104:2923–2931. doi:10.1161/hc4901.100526

    Article  CAS  PubMed  Google Scholar 

  29. Ichihara S, Obata K, Yamada Y, Nagata K, Noda A, Ichihara G et al (2006) Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors. J Mol Cell Cardiol 41:318–329. doi:10.1016/j.yjmcc.2006.05.013

    Article  CAS  PubMed  Google Scholar 

  30. Brigadeau F, Gele P, Wibaux M, Marquie C, Martin-Nizard F, Torpier G et al (2007) The PPARalpha activator fenofibrate slows down the progression of the left ventricular dysfunction in porcine tachycardia-induced cardiomyopathy. J Cardiovasc Pharmacol 49:408–415. doi:10.1097/FJC.0b013e3180544540

    Article  CAS  PubMed  Google Scholar 

  31. Schupp M, Kintscher U, Fielitz J, Thomas J, Pregla R, Hetzer R et al (2006) Cardiac PPARalpha expression in patients with dilated cardiomyopathy. Eur J Heart Fail 8:290–294. doi:10.1016/j.ejheart.2005.09.003

    Article  CAS  PubMed  Google Scholar 

  32. Ding G, Fu M, Qin Q, Lewis W, Kim HW, Fukai T et al (2007) Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage. Cardiovasc Res 76:269–279. doi:10.1016/j.cardiores.2007.06.027

    Article  CAS  PubMed  Google Scholar 

  33. Mehrabi MR, Haslmayer P, Humpeler S, Strauss-Blasche G, Marktl W, Tamaddon F et al (2003) Quantitative analysis of peroxisome proliferator-activated receptor gamma (PPARgamma) expression in arteries and hearts of patients with ischaemic or dilated cardiomyopathy. Eur J Heart Fail 5:733–739. doi:10.1016/S1388-9842(03)00148-X

    Article  CAS  PubMed  Google Scholar 

  34. Finck BN, Kelly DP (2002) Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart. J Mol Cell Cardiol 34:1249–1257. doi:10.1006/jmcc.2002.2061

    Article  PubMed  Google Scholar 

  35. Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL et al (2005) A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes. Cell Metab 1:133–144. doi:10.1016/j.cmet.2005.01.006

    Article  CAS  PubMed  Google Scholar 

  36. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A et al (2002) The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130

    CAS  PubMed  Google Scholar 

  37. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J et al (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80. doi:10.1038/79839

    Article  CAS  PubMed  Google Scholar 

  38. Andrulionyte L, Zacharova J, Chiasson JL, Laakso M (2004) Common polymorphisms of the PPAR-gamma2 (Pro12Ala) and PGC-1alpha (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial. Diabetologia 47:2176–2184. doi:10.1007/s00125-004-1577-2

    Article  CAS  PubMed  Google Scholar 

  39. Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J et al (1998) A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284–287. doi:10.1038/3099

    Article  CAS  PubMed  Google Scholar 

  40. Meshkani R, Taghikhani M, Larijani B, Bahrami Y, Khatami S, Khoshbin E et al (2007) Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPARgamma-2) gene is associated with greater insulin sensitivity and decreased risk of type 2 diabetes in an Iranian population. Clin Chem Lab Med 45:477–482. doi:10.1515/CCLM.2007.095

    Article  CAS  PubMed  Google Scholar 

  41. Nemoto M, Sasaki T, Deeb SS, Fujimoto WY, Tajima N (2002) Differential effect of PPARgamma2 variants in the development of type 2 diabetes between native Japanese and Japanese Americans. Diabetes Res Clin Pract 57:131–137. doi:10.1016/S0168-8227(02)00027-X

    Article  CAS  PubMed  Google Scholar 

  42. Tai ES, Corella D, urenberg-Yap M, Adiconis X, Chew SK, Tan CE et al (2004) Differential effects of the C1431T and Pro12Ala PPARgamma gene variants on plasma lipids and diabetes risk in an Asian population. J Lipid Res 45:674–685. doi:10.1194/jlr.M300363-JLR200

    Article  CAS  PubMed  Google Scholar 

  43. Flavell DM, Ireland H, Stephens JW, Hawe E, Acharya J, Mather H et al (2005) Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes. Diabetes 54:582–586. doi:10.2337/diabetes.54.2.582

    Article  CAS  PubMed  Google Scholar 

  44. Kang ES, Park SY, Kim HJ, Kim CS, Ahn CW, Cha BS et al (2005) Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther 78:202–208. doi:10.1016/j.clpt.2005.04.013

    Article  CAS  PubMed  Google Scholar 

  45. Wolford JK, Yeatts KA, Dhanjal SK, Black MH, Xiang AH, Buchanan TA et al (2005) Sequence variation in PPARG may underlie differential response to troglitazone. Diabetes 54:3319–3325. doi:10.2337/diabetes.54.11.3319

    Article  CAS  PubMed  Google Scholar 

  46. Hansen L, Ekstrom CT, Tabanera YP, Anant M, Wassermann K, Reinhardt RR (2006) The Pro12Ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients. J Clin Endocrinol Metab 91:3446–3450. doi:10.1210/jc.2006-0590

    Article  CAS  PubMed  Google Scholar 

  47. Sambandam N, Morabito D, Wagg C, Finck BN, Kelly DP, Lopaschuk GD (2006) Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia. Am J Physiol Heart Circ Physiol 290:H87–H95. doi:10.1152/ajpheart.00285.2005

    Article  CAS  PubMed  Google Scholar 

  48. Panagia M, Gibbons GF, Radda GK, Clarke K (2005) PPAR-alpha activation required for decreased glucose uptake and increased susceptibility to injury during ischemia. Am J Physiol Heart Circ Physiol 288:H2677–H2683. doi:10.1152/ajpheart.00200.2004

    Article  CAS  PubMed  Google Scholar 

  49. Lygate CA, Hulbert K, Monfared M, Cole MA, Clarke K, Neubauer S (2003) The PPARgamma-activator rosiglitazone does not alter remodeling but increases mortality in rats post-myocardial infarction. Cardiovasc Res 58:632–637. doi:10.1016/S0008-6363(03)00289-X

    Article  CAS  PubMed  Google Scholar 

  50. Yue TL, Bao W, Gu JL, Cui J, Tao L, Ma XL et al (2005) Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes 54:554–562. doi:10.2337/diabetes.54.2.554

    Article  CAS  PubMed  Google Scholar 

  51. Liu HR, Tao L, Gao E, Lopez BL, Christopher TA, Willette RN et al (2004) Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovasc Res 62:135–144. doi:10.1016/j.cardiores.2003.12.027

    Article  CAS  PubMed  Google Scholar 

  52. Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A (2004) The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care 27:1647–1653. doi:10.2337/diacare.27.7.1647

    Article  PubMed  Google Scholar 

  53. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK et al (2005) 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 366:1279–1289. doi:10.1016/S0140-6736(05)67528-9

    Article  CAS  PubMed  Google Scholar 

  54. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (2007) Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. J Am Med Assoc 298:1180–1188. doi:10.1001/jama.298.10.1180

    Article  CAS  Google Scholar 

  55. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471. doi:10.1056/NEJMoa072761

    Article  CAS  PubMed  Google Scholar 

  56. Koskinen P, Manttari M, Manninen V, Huttunen JK, Heinonen OP, Frick MH (1992) Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 15:820–825. doi:10.2337/diacare.15.7.820

    Article  CAS  PubMed  Google Scholar 

  57. Flavell DM, Jamshidi Y, Hawe E, Pineda TI, Taskinen MR, Frick MH (2002) Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease. Circulation 105:1440–1445. doi:10.1161/01.CIR.0000012145.80593.25

    Article  CAS  PubMed  Google Scholar 

  58. Cresci S, Jones PG, Sucharov CC, Marsh S, Lanfear DE, Garsa A et al (2008) Interaction between PPARA genotype and β-blocker treatment influences clinical outcomes following acute coronary syndromes. Pharmacogenetics 9(10):1403–1417. doi:10.2217/14622416.9.10.1403

    CAS  Google Scholar 

  59. Sapone A, Peters JM, Sakai S, Tomita S, Papiha SS, Dai R et al (2000) The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants. Pharmacogenetics 10:321–333. doi:10.1097/00008571-200006000-00006

    Article  CAS  PubMed  Google Scholar 

  60. Flavell DM, Pineda TI, Jamshidi Y, Evans D, Diamond JR, Elkeles RS et al (2000) Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects. Diabetologia 43:673–680. doi:10.1007/s001250051357

    Article  CAS  PubMed  Google Scholar 

  61. Vohl MC, Lepage P, Gaudet D, Brewer CG, Betard C, Perron P et al (2000) Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia. J Lipid Res 41:945–952

    CAS  PubMed  Google Scholar 

  62. Tai ES, Demissie S, Cupples LA, Corella D, Wilson PW, Schaefer EJ et al (2002) Association between the PPARA L162 V polymorphism and plasma lipid levels the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 22:805–810. doi:10.1161/01.ATV.0000012302.11991.42

    Article  CAS  PubMed  Google Scholar 

  63. Tai ES, Corella D, Demissie S, Cupples LA, Coltell O, Schaefer EJ et al (2005) Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglyceride and apolipoprotein C-III concentrations in the Framingham Heart Study. J Nutr 135:397–403

    CAS  PubMed  Google Scholar 

  64. Pischon T, Pai JK, Manson JE, Hu FB, Rexrode KM, Hunter D et al (2005) Peroxisome proliferator-activated receptor-gamma2 P12A polymorphism and risk of coronary heart disease in US men and women. Arterioscler Thromb Vasc Biol 25:1654–1658. doi:10.1161/01.ATV.0000171993.78135.7e

    Article  CAS  PubMed  Google Scholar 

  65. Doney AS, Fischer B, Leese G, Morris AD, Palmer CN (2004) Cardiovascular risk in type 2 diabetes is associated with variation at the PPARG locus: a Go-DARTS study. Arterioscler Thromb Vasc Biol 24:2403–2407. doi:10.1161/01.ATV.0000147897.57527.e4

    Article  CAS  PubMed  Google Scholar 

  66. Ridker PM, Cook NR, Cheng S, Erlich HA, Lindpaintner K, Plutzky J et al (2003) Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction. Arterioscler Thromb Vasc Biol 23:859–863. doi:10.1161/01.ATV.0000068680.19521.34

    Article  CAS  PubMed  Google Scholar 

  67. (1989) Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. New Engl J Med 321:129–135

  68. Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Lebel P, Dallongeville J et al (1998) A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans. Hum Mol Genet 7:435–440. doi:10.1093/hmg/7.3.435

    Article  CAS  PubMed  Google Scholar 

  69. Wang XL, Oosterhof J, Duarte N (1999) Peroxisome proliferator-activated receptor gamma C161–>T polymorphism and coronary artery disease. Cardiovasc Res 44:588–594. doi:10.1016/S0008-6363(99)00256-4

    Article  CAS  PubMed  Google Scholar 

  70. Al-Shali KZ, House AA, Hanley AJ, Khan HM, Harris SB, Zinman B et al (2004) Genetic variation in PPARG encoding peroxisome proliferator-activated receptor gamma associated with carotid atherosclerosis. Stroke 35:2036–2040. doi:10.1161/01.STR.0000138784.68159.a5

    Article  CAS  PubMed  Google Scholar 

  71. Chao TH, Li YH, Chen JH, Wu HL, Shi GY, Liu PY et al (2004) The 161TT genotype in the exon 6 of the peroxisome-proliferator-activated receptor gamma gene is associated with premature acute myocardial infarction and increased lipid peroxidation in habitual heavy smokers. Clin Sci (London, England) 107:461–466. doi:10.1042/CS20040014

    CAS  Google Scholar 

  72. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ et al (2005) Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia 48:2482–2485. doi:10.1007/s00125-005-0029-y

    Article  CAS  PubMed  Google Scholar 

  73. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ et al (2004) Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364:685–696. doi:10.1016/S0140-6736(04)16895-5

    Article  CAS  PubMed  Google Scholar 

  74. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et al (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 352:1425–1435. doi:10.1056/NEJMoa050461

    Article  CAS  PubMed  Google Scholar 

  75. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S et al (2006) Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 29:1220–1226. doi:10.2337/dc05-2465

    Article  CAS  PubMed  Google Scholar 

  76. Waters DD, LaRosa JC, Barter P, Fruchart JC, Gotto AM Jr, Carter R et al (2006) Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J Am Coll Cardiol 48:1793–1799. doi:10.1016/j.jacc.2006.07.041

    Article  CAS  PubMed  Google Scholar 

  77. Steiner G (2005) A new perspective in the treatment of dyslipidemia: can fenofibrate offer unique benefits in the treatment of type 2 diabetes mellitus? Treat Endocrinol 4:311–317. doi:10.2165/00024677-200504050-00004

    Article  CAS  PubMed  Google Scholar 

  78. Steiner G (2000) Lipid intervention trials in diabetes. Diabetes Care 23(Suppl 2):B49–B53

    PubMed  Google Scholar 

  79. Zelvyte I, Dominaitiene R, Crisby M, Janciauskiene S (2002) Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res 45:147–154. doi:10.1006/phrs.2001.0922

    Article  CAS  PubMed  Google Scholar 

  80. Inoue I, Goto S, Mizotani K, Awata T, Mastunaga T, Kawai S et al (2000) Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells. Life Sci 67:863–876. doi:10.1016/S0024-3205(00)00680-9

    Article  CAS  PubMed  Google Scholar 

  81. Chen S, Tsybouleva N, Ballantyne CM, Gotto AM Jr, Marian AJ (2004) Effects of PPARalpha, gamma and delta haplotypes on plasma levels of lipids, severity and progression of coronary atherosclerosis and response to statin therapy in the lipoprotein coronary atherosclerosis study. Pharmacogenetics 14:61–71. doi:10.1097/00008571-200401000-00007

    Article  CAS  PubMed  Google Scholar 

  82. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O et al (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1:259–271. doi:10.1016/j.cmet.2005.03.002

    Article  CAS  PubMed  Google Scholar 

  83. Lehman JJ, Kelly DP (2002) Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart. Clin Exp Pharmacol Physiol 29:339–345. doi:10.1046/j.1440-1681.2002.03655.x

    Article  CAS  PubMed  Google Scholar 

  84. Wang S, Fu C, Wang H, Shi Y, Xu X, Chen J et al (2007) Polymorphisms of the peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene are associated with hypertrophic cardiomyopathy and not with hypertension hypertrophy. Clin Chem Lab Med 45(8):962–967. doi:10.1515/CCLM.2007.189

    Article  CAS  PubMed  Google Scholar 

  85. Ambye L, Rasmussen S, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S et al (2005) Studies of the Gly482Ser polymorphism of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) gene in Danish subjects with the metabolic syndrome. Diabetes Res Clin Pract 67:175–179. doi:10.1016/j.diabres.2004.06.013

    Article  CAS  PubMed  Google Scholar 

  86. Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ et al (2001) Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natil Acad Sci USA 98:3820–3825. doi:10.1073/pnas.061035098

    Google Scholar 

  87. Yoon JC, Xu G, Deeney JT, Yang SN, Rhee J, Puigserver P et al (2003) Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. Dev Cell 5:73–83. doi:10.1016/S1534-5807(03)00170-9

    Article  CAS  PubMed  Google Scholar 

  88. Petrovic MG, Kunej T, Peterlin B, Dovc P, Petrovic D (2005) Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-gamma coactivator-1 gene might be a risk factor for diabetic retinopathy in Slovene population (Caucasians) with type 2 diabetes and the Pro12Ala polymorphism of the PPARgamma gene is not. Diabetes/Metab Res Rev 21:470–474. doi:10.1002/dmrr.546

    Article  CAS  Google Scholar 

  89. Kunej T, Globocnik PM, Dovc P, Peterlin B, Petrovic DA (2004) Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with type 2 diabetes in Caucasians. Folia Biol 50:157–158

    CAS  Google Scholar 

  90. Huss JM, Imahashi K, Dufour CR, Weinheimer CJ, Courtois M, Kovacs A et al (2007) The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab 6:25–37. doi:10.1016/j.cmet.2007.06.005

    Article  CAS  PubMed  Google Scholar 

  91. Alaynick WA, Kondo RP, Xie W, He W, Dufour CR, Downes M et al (2007) ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab 6:13–24. doi:10.1016/j.cmet.2007.06.007

    Article  CAS  PubMed  Google Scholar 

  92. Pollak A, Rokach A, Blumenfeld A, Rosen LJ, Resnik L, Dresner PR (2004) Association of oestrogen receptor alpha gene polymorphism with the angiographic extent of coronary artery disease. Eur Heart J 25:240–245. doi:10.1016/j.ehj.2003.10.028

    Article  CAS  PubMed  Google Scholar 

  93. Kunnas TA, Laippala P, Penttila A, Lehtimaki T, Karhunen PJ (2000) Association of polymorphism of human alpha oestrogen receptor gene with coronary artery disease in men: a necropsy study. BMJ (Clinical Research Ed) 321:273–274. doi:10.1136/bmj.321.7256.273

    Article  CAS  Google Scholar 

  94. Figtree GA, Kindmark A, Lind L, Grundberg E, Speller B, Robinson BG et al (2007) Novel estrogen receptor alpha promoter polymorphism increases ventricular hypertrophic response to hypertension. J Steroid Biochem Mol Biol 103:110–118. doi:10.1016/j.jsbmb.2006.09.035

    Article  CAS  PubMed  Google Scholar 

  95. Malmqvist K, Kahan T, Edner M, Held C, Hagg A, Lind L et al (2001) Regression of left ventricular hypertrophy in human hypertension with irbesartan. J Hypertens 19:1167–1176. doi:10.1097/00004872-200106000-00023

    Article  CAS  PubMed  Google Scholar 

  96. Peter I, Shearman AM, Vasan RS, Zucker DR, Schmid CH, Demissie S et al (2005) Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women. Am J Hypertens 18:1388–1395. doi:10.1016/j.amjhyper.2005.05.023

    Article  CAS  PubMed  Google Scholar 

  97. Nohara A, Kawashiri MA, Claudel T, Mizuno M, Tsuchida M, Takata M et al (2007) High frequency of a retinoid X receptor gamma gene variant in familial combined hyperlipidemia that associates with atherogenic dyslipidemia. Arterioscler Thromb Vasc Biol 27:923–928. doi:10.1161/01.ATV.0000258945.76141.8a

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Funding: (SC): NIH SCCOR in Cardiac Dysfunction and Disease P50 HL077113, 5 P60 DK20579 and 1R21HL089681.

Author information

Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8086, Saint Louis, MO, 63110-1093, USA

    Neville F. Mistry & Sharon Cresci

Authors
  1. Neville F. Mistry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharon Cresci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sharon Cresci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mistry, N.F., Cresci, S. PPAR transcriptional activator complex polymorphisms and the promise of individualized therapy for heart failure. Heart Fail Rev 15, 197–207 (2010). https://doi.org/10.1007/s10741-008-9114-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-008-9114-x

Keywords

Search

Navigation