Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases
Abstract
:1. Introduction
2. Biological Role and Tissue-Specific Expression of PPARs
3. The Role of PPARs in Cardiac Diseases
4. Therapeutic Potential of PPAR Agonists in Cardiac Diseases
4.1. Studies in Animal Models
4.2. Clinical Studies
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AMPK | AMP kinase |
BAT | brown adipose tissue |
BF | bezafibrate |
BTHS | Barth syndrome |
CHD | coronary heart disease |
CPT | carnitine palmitoyltransferase |
CyP-D | cyclophilin D |
FAO | fatty acid oxidation |
HF | heart failure |
MI NRF | myocardial infarction nuclear respiratory factors |
PGC-1α | proliferator-activated receptor gamma coactivator-1 alpha |
PPAR | peroxisome proliferator-activated receptor |
TAC | transverse aortic constriction |
References
- Schmidt, A.; Endo, N.; Rutledge, S.J.; Vogel, R.; Shinar, D.; Rodan, G.A. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol. Endocrinol. 1992, 6, 1634–1641. [Google Scholar] [CrossRef] [PubMed]
- Dreyer, C.; Krey, G.; Keller, H.; Givel, F.; Helftenbein, G.; Wahli, W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 1992, 68, 879–887. [Google Scholar] [CrossRef]
- Issemann, I.; Green, S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990, 347, 645–650. [Google Scholar] [CrossRef] [PubMed]
- Eleff, S.; Kennaway, N.G.; Buist, N.R.; Darley-Usmar, V.M.; Capaldi, R.A.; Bank, W.J.; Chance, B. 31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle. Proc. Natl. Acad. Sci. USA 1984, 81, 3529–3533. [Google Scholar] [CrossRef] [PubMed]
- Ledermann, H.; Kaufmann, B. Comparative pharmacokinetics of 400 mg bezafibrate after a single oral administration of a new slow-release preparation and the currently available commercial form. J. Int. Med. Res. 1981, 9, 516–520. [Google Scholar] [CrossRef] [PubMed]
- Olsson, A.G.; Lang, P.D. Dose-response study of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinanemia. Atherosclerosis 1978, 31, 421–428. [Google Scholar] [CrossRef]
- Nolte, R.T.; Wisely, G.B.; Westin, S.; Cobb, J.E.; Lambert, M.H.; Kurokawa, R.; Rosenfeld, M.G.; Willson, T.M.; Glass, C.K.; Milburn, M.V. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998, 395, 137–143. [Google Scholar] [CrossRef] [PubMed]
- Xu, H.E.; Lambert, M.H.; Montana, V.G.; Parks, D.J.; Blanchard, S.G.; Brown, P.J.; Sternbach, D.D.; Lehmann, J.M.; Wisely, G.B.; Willson, T.M.; et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell 1999, 3, 397–403. [Google Scholar] [CrossRef]
- Komen, J.C.; Thorburn, D.R. Turn up the power—Pharmacological activation of mitochondrial biogenesis in mouse models. Br. J. Pharmacol. 2014, 171, 1818–1836. [Google Scholar] [CrossRef] [PubMed]
- Lam, V.Q.; Zheng, J.; Griffin, P.R. Unique Interactome Network Signatures for Peroxisome Proliferator-activated Receptor Gamma (PPARgamma) Modulation by Functional Selective Ligands. Mol. Cell. Proteom. 2017, 16, 2098–2110. [Google Scholar] [CrossRef] [PubMed]
- Sookoian, S.; Pirola, C.J. Elafibranor for the treatment of NAFLD: One pill, two molecular targets and multiple effects in a complex phenotype. Ann. Hepatol. 2016, 15, 604–609. [Google Scholar] [PubMed]
- Chandra, V.; Huang, P.; Hamuro, Y.; Raghuram, S.; Wang, Y.; Burris, T.P.; Rastinejad, F. Structure of the intact PPAR-gamma-RXR-nuclear receptor complex on DNA. Nature 2008, 456, 350–356. [Google Scholar] [CrossRef] [PubMed]
- Braissant, O.; Foufelle, F.; Scotto, C.; Dauca, M.; Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 1996, 137, 354–366. [Google Scholar] [CrossRef] [PubMed]
- Auboeuf, D.; Rieusset, J.; Fajas, L.; Vallier, P.; Frering, V.; Riou, J.P.; Staels, B.; Auwerx, J.; Laville, M.; Vidal, H. 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, 46, 1319–1327. [Google Scholar] [CrossRef] [PubMed]
- Abbott, B.D. Review of the expression of peroxisome proliferator-activated receptors alpha (PPAR alpha), beta (PPAR beta), and gamma (PPAR gamma) in rodent and human development. Reprod. Toxicol. 2009, 27, 246–257. [Google Scholar] [CrossRef] [PubMed]
- Grygiel-Gorniak, B. Peroxisome proliferator-activated receptors and their ligands: Nutritional and clinical implications—A review. Nutr. J. 2014, 13, 17. [Google Scholar] [CrossRef] [PubMed]
- Sertznig, P.; Seifert, M.; Tilgen, W.; Reichrath, J. Present concepts and future outlook: Function of peroxisome proliferator-activated receptors (PPARs) for pathogenesis, progression, and therapy of cancer. J. Cell. Physiol. 2007, 212, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Willson, T.M.; Brown, P.J.; Sternbach, D.D.; Henke, B.R. The PPARs: From orphan receptors to drug discovery. J. Med. Chem. 2000, 43, 527–550. [Google Scholar] [CrossRef] [PubMed]
- Tenenbaum, A.; Fisman, E.Z. Balanced pan-PPAR activator bezafibrate in combination with statin: Comprehensive lipids control and diabetes prevention? Cardiovasc. Diabetol. 2012, 11, 140. [Google Scholar] [CrossRef] [PubMed]
- Kelly, D.P.; Scarpulla, R.C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 2004, 18, 357–368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huss, J.M.; Kelly, D.P. Mitochondrial energy metabolism in heart failure: A question of balance. J. Clin. Investig. 2005, 115, 547–555. [Google Scholar] [CrossRef] [PubMed]
- Ventura-Clapier, R.; Garnier, A.; Veksler, V. Transcriptional control of mitochondrial biogenesis: The central role of PGC-1alpha. Cardiovasc. Res. 2008, 79, 208–217. [Google Scholar] [CrossRef] [PubMed]
- Zong, H.; Ren, J.M.; Young, L.H.; Pypaert, M.; Mu, J.; Birnbaum, M.J.; Shulman, G.I. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl. Acad. Sci. USA 2002, 99, 15983–15987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Reznick, R.M.; Shulman, G.I. The role of AMP-activated protein kinase in mitochondrial biogenesis. J. Physiol. 2006, 574, 33–39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jager, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. USA 2007, 104, 12017–12022. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Watanabe, K.; Fujii, H.; Takahashi, T.; Kodama, M.; Aizawa, Y.; Ohta, Y.; Ono, T.; Hasegawa, G.; Naito, M.; Nakajima, T.; et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity. J. Biol. Chem. 2000, 275, 22293–22299. [Google Scholar] [CrossRef] [PubMed]
- Campbell, F.M.; Kozak, R.; Wagner, A.; Altarejos, J.Y.; Dyck, J.R.; Belke, D.D.; Severson, D.L.; Kelly, D.P.; Lopaschuk, G.D. A role for peroxisome proliferator-activated receptor alpha (PPARalpha) in the control of cardiac malonyl-CoA levels: Reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase. J. Biol. Chem. 2002, 277, 4098–4103. [Google Scholar] [CrossRef] [PubMed]
- Loichot, C.; Jesel, L.; Tesse, A.; Tabernero, A.; Schoonjans, K.; Roul, G.; Carpusca, I.; Auwerx, J.; Andriantsitohaina, R. Deletion of peroxisome proliferator-activated receptor-alpha induces an alteration of cardiac functions. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H161–H166. [Google Scholar] [CrossRef] [PubMed]
- Guellich, A.; Damy, T.; Conti, M.; Claes, V.; Samuel, J.L.; Pineau, T.; Lecarpentier, Y.; Coirault, C. Tempol prevents cardiac oxidative damage and left ventricular dysfunction in the PPAR-alpha KO mouse. Am. J. Physiol. Heart Circ. Physiol. 2013, 304, H1505–H1512. [Google Scholar] [CrossRef] [PubMed]
- Luptak, I.; Balschi, J.A.; Xing, Y.; Leone, T.C.; Kelly, D.P.; Tian, R. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation 2005, 112, 2339–2346. [Google Scholar] [CrossRef] [PubMed]
- Smeets, P.J.; Teunissen, B.E.; Willemsen, P.H.; van Nieuwenhoven, F.A.; Brouns, A.E.; Janssen, B.J.; Cleutjens, J.P.; Staels, B.; van der Vusse, G.J.; van Bilsen, M. Cardiac hypertrophy is enhanced in PPAR alpha-/- mice in response to chronic pressure overload. Cardiovasc. Res. 2008, 78, 79–89. [Google Scholar] [CrossRef] [PubMed]
- Oka, S.; Alcendor, R.; Zhai, P.; Park, J.Y.; Shao, D.; Cho, J.; Yamamoto, T.; Tian, B.; Sadoshima, J. PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 2011, 14, 598–611. [Google Scholar] [CrossRef] [PubMed]
- Finck, B.N.; Lehman, J.J.; Leone, T.C.; Welch, M.J.; Bennett, M.J.; Kovacs, A.; Han, X.; Gross, R.W.; Kozak, R.; Lopaschuk, G.D.; et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J. Clin. Investig. 2002, 109, 121–130. [Google Scholar] [CrossRef] [PubMed]
- Kaimoto, S.; Hoshino, A.; Ariyoshi, M.; Okawa, Y.; Tateishi, S.; Ono, K.; Uchihashi, M.; Fukai, K.; Iwai-Kanai, E.; Matoba, S. Activation of PPAR-alpha in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure. Am. J. Physiol. Heart Circ. Physiol. 2017, 312, H305–H313. [Google Scholar] [CrossRef] [PubMed]
- Garnier, A.; Fortin, D.; Delomenie, C.; Momken, I.; Veksler, V.; Ventura-Clapier, R. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J. Physiol. 2003, 551, 491–501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Javadov, S.; Purdham, D.M.; Zeidan, A.; Karmazyn, M. NHE-1 inhibition improves cardiac mitochondrial function through regulation of mitochondrial biogenesis during postinfarction remodeling. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H1722–H1730. [Google Scholar] [CrossRef] [PubMed]
- Sebastiani, M.; Giordano, C.; Nediani, C.; Travaglini, C.; Borchi, E.; Zani, M.; Feccia, M.; Mancini, M.; Petrozza, V.; Cossarizza, A.; et al. Induction of mitochondrial biogenesis is a maladaptive mechanism in mitochondrial cardiomyopathies. J. Am. Coll. Cardiol. 2007, 50, 1362–1369. [Google Scholar] [CrossRef] [PubMed]
- Sack, M.N.; Rader, T.A.; Park, S.; Bastin, J.; McCune, S.A.; Kelly, D.P. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 1996, 94, 2837–2842. [Google Scholar] [CrossRef] [PubMed]
- Burns, K.A.; Vanden Heuvel, J.P. Modulation of PPAR activity via phosphorylation. Biochim. Biophys. Acta 2007, 1771, 952–960. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lazennec, G.; Canaple, L.; Saugy, D.; Wahli, W. Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators. Mol. Endocrinol. 2000, 14, 1962–1975. [Google Scholar] [CrossRef] [PubMed]
- Barger, P.M.; Browning, A.C.; Garner, A.N.; Kelly, D.P. p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: A potential role in the cardiac metabolic stress response. J. Biol. Chem. 2001, 276, 44495–44501. [Google Scholar] [CrossRef] [PubMed]
- Barger, P.M.; Brandt, J.M.; Leone, T.C.; Weinheimer, C.J.; Kelly, D.P. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J. Clin. Investig. 2000, 105, 1723–1730. [Google Scholar] [CrossRef] [PubMed]
- Shalev, A.; Siegrist-Kaiser, C.A.; Yen, P.M.; Wahli, W.; Burger, A.G.; Chin, W.W.; Meier, C.A. The peroxisome proliferator-activated receptor alpha is a phosphoprotein: Regulation by insulin. Endocrinology 1996, 137, 4499–4502. [Google Scholar] [CrossRef] [PubMed]
- Adams, M.; Reginato, M.J.; Shao, D.; Lazar, M.A.; Chatterjee, V.K. Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J. Biol. Chem. 1997, 272, 5128–5132. [Google Scholar] [CrossRef] [PubMed]
- Lopaschuk, G.D.; Ussher, J.R.; Folmes, C.D.; Jaswal, J.S.; Stanley, W.C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 2010, 90, 207–258. [Google Scholar] [CrossRef] [PubMed]
- Arad, M.; Seidman, C.E.; Seidman, J.G. AMP-activated protein kinase in the heart: Role during health and disease. Circ. Res. 2007, 100, 474–488. [Google Scholar] [CrossRef] [PubMed]
- Yoon, M.J.; Lee, G.Y.; Chung, J.J.; Ahn, Y.H.; Hong, S.H.; Kim, J.B. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 2006, 55, 2562–2570. [Google Scholar] [CrossRef] [PubMed]
- Barreto-Torres, G.; Parodi-Rullan, R.; Javadov, S. The role of PPARalpha in metformin-induced attenuation of mitochondrial dysfunction in acute cardiac ischemia/reperfusion in rats. Int. J. Mol. Sci. 2012, 13, 7694–7709. [Google Scholar] [CrossRef] [PubMed]
- Barreto-Torres, G.; Hernandez, J.S.; Jang, S.; Rodriguez-Munoz, A.R.; Torres-Ramos, C.A.; Basnakian, A.G.; Javadov, S. The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPARalpha-cyclophilin D interaction in cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 2015, 308, H749–H758. [Google Scholar] [CrossRef] [PubMed]
- Barreto-Torres, G.; Javadov, S. Possible Role of Interaction between PPARalpha and Cyclophilin D in Cardioprotection of AMPK against In Vivo Ischemia-Reperfusion in Rats. PPAR Res. 2016, 2016, 9282087. [Google Scholar] [CrossRef] [PubMed]
- Duan, S.Z.; Ivashchenko, C.Y.; Russell, M.W.; Milstone, D.S.; Mortensen, R.M. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice. Circ. Res. 2005, 97, 372–379. [Google Scholar] [CrossRef] [PubMed]
- Barbieri, M.; Di Filippo, C.; Esposito, A.; Marfella, R.; Rizzo, M.R.; D’Amico, M.; Ferraraccio, F.; Di Ronza, C.; Duan, S.Z.; Mortensen, R.M.; et al. Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-gamma-knockout (CM-PGKO) mice. PLoS ONE 2012, 7, e35999. [Google Scholar] [CrossRef] [PubMed]
- Luo, J.; Wu, S.; Liu, J.; Li, Y.; Yang, H.; Kim, T.; Zhelyabovska, O.; Ding, G.; Zhou, Y.; Yang, Y.; et al. Conditional PPARgamma knockout from cardiomyocytes of adult mice impairs myocardial fatty acid utilization and cardiac function. Am. J. Transl. Res. 2010, 3, 61–72. [Google Scholar] [PubMed]
- Ding, G.; Fu, M.; Qin, Q.; Lewis, W.; Kim, H.W.; Fukai, T.; Bacanamwo, M.; Chen, Y.E.; Schneider, M.D.; Mangelsdorf, D.J.; et al. Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage. Cardiovasc. Res. 2007, 76, 269–279. [Google Scholar] [CrossRef] [PubMed]
- Son, N.H.; Park, T.S.; Yamashita, H.; Yokoyama, M.; Huggins, L.A.; Okajima, K.; Homma, S.; Szabolcs, M.J.; Huang, L.S.; Goldberg, I.J. Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice. J. Clin. Investig. 2007, 117, 2791–2801. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Wang, P.; Luo, J.; Huang, Y.; He, L.; Yang, H.; Li, Q.; Wu, S.; Zhelyabovska, O.; Yang, Q. Peroxisome proliferator-activated receptor beta/delta activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition. Hypertension 2011, 57, 223–230. [Google Scholar] [CrossRef] [PubMed]
- Jucker, B.M.; Doe, C.P.; Schnackenberg, C.G.; Olzinski, A.R.; Maniscalco, K.; Williams, C.; Hu, T.C.; Lenhard, S.C.; Costell, M.; Bernard, R.; et al. PPARdelta activation normalizes cardiac substrate metabolism and reduces right ventricular hypertrophy in congestive heart failure. J. Cardiovasc. Pharmacol. 2007, 50, 25–34. [Google Scholar] [CrossRef] [PubMed]
- Pol, C.J.; Lieu, M.; Drosatos, K. PPARs: Protectors or Opponents of Myocardial Function? PPAR Res. 2015, 2015, 835985. [Google Scholar] [CrossRef] [PubMed]
- Parodi-Rullan, R.M.; Chapa-Dubocq, X.R.; Javadov, S. Acetylation of Mitochondrial Proteins in the Heart: The Role of SIRT3. Front. Physiol. 2018, 9, 1094. [Google Scholar] [CrossRef] [PubMed]
- Jiang, X.; Ye, X.; Guo, W.; Lu, H.; Gao, Z. Inhibition of HDAC3 promotes ligand-independent PPARgamma activation by protein acetylation. J. Mol. Endocrinol. 2014, 53, 191–200. [Google Scholar] [CrossRef] [PubMed]
- Montgomery, R.L.; Potthoff, M.J.; Haberland, M.; Qi, X.; Matsuzaki, S.; Humphries, K.M.; Richardson, J.A.; Bassel-Duby, R.; Olson, E.N. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J. Clin. Investig. 2008, 118, 3588–3597. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Diezko, R.; Suske, G. Ligand binding reduces SUMOylation of the peroxisome proliferator-activated receptor gamma (PPARgamma) activation function 1 (AF1) domain. PLoS ONE 2013, 8, e66947. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.H.; Park, K.W.; Lee, E.W.; Jang, W.S.; Seo, J.; Shin, S.; Hwang, K.A.; Song, J. Suppression of PPARgamma through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation. Cell Death Differ. 2014, 21, 594–603. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez, J.E.; Liao, J.Y.; He, J.; Schisler, J.C.; Newgard, C.B.; Drujan, D.; Glass, D.J.; Frederick, C.B.; Yoder, B.C.; Lalush, D.S.; et al. The ubiquitin ligase MuRF1 regulates PPARalpha activity in the heart by enhancing nuclear export via monoubiquitination. Mol. Cell. Endocrinol. 2015, 413, 36–48. [Google Scholar] [CrossRef] [PubMed]
- Qian, Y.; Li, P.; Zhang, J.; Shi, Y.; Chen, K.; Yang, J.; Wu, Y.; Ye, X. Association between peroxisome proliferator-activated receptor-alpha, delta, and gamma polymorphisms and risk of coronary heart disease: A case-control study and meta-analysis. Medicine (Baltimore) 2016, 95, e4299. [Google Scholar] [CrossRef] [PubMed]
- Rudkowska, I.; Verreault, M.; Barbier, O.; Vohl, M.C. Differences in transcriptional activation by the two allelic (L162V Polymorphic) variants of PPARalpha after Omega-3 fatty acids treatment. PPAR Res. 2009, 2009, 369602. [Google Scholar] [CrossRef] [PubMed]
- Tai, E.S.; Corella, D.; Demissie, S.; Cupples, L.A.; Coltell, O.; Schaefer, E.J.; Tucker, K.L.; Ordovas, J.M. 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. 2005, 135, 397–403. [Google Scholar] [CrossRef] [PubMed]
- Reinhard, W.; Stark, K.; Sedlacek, K.; Fischer, M.; Baessler, A.; Neureuther, K.; Weber, S.; Kaess, B.; Wiedmann, S.; Mitsching, S.; et al. Association between PPARalpha gene polymorphisms and myocardial infarction. Clin. Sci. (Lond.) 2008, 115, 301–308. [Google Scholar] [CrossRef] [PubMed]
- Ingwall, J.S. Energy metabolism in heart failure and remodelling. Cardiovasc. Res. 2009, 81, 412–419. [Google Scholar] [CrossRef] [PubMed]
- Neubauer, S. The failing heart—An engine out of fuel. N. Engl. J. Med. 2007, 356, 1140–1151. [Google Scholar] [CrossRef] [PubMed]
- Stanley, W.C.; Recchia, F.A.; Lopaschuk, G.D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 2005, 85, 1093–1129. [Google Scholar] [CrossRef] [PubMed]
- Xiong, D.; He, H.; James, J.; Tokunaga, C.; Powers, C.; Huang, Y.; Osinska, H.; Towbin, J.A.; Purevjav, E.; Balschi, J.A.; et al. Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance. Am. J. Physiol. Heart Circ. Physiol. 2014, 306, H326–H338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Exil, V.J.; Gardner, C.D.; Rottman, J.N.; Sims, H.; Bartelds, B.; Khuchua, Z.; Sindhal, R.; Ni, G.; Strauss, A.W. Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking very-long-chain acyl-CoA dehydrogenase. Am. J. Physiol. Heart Circ. Physiol. 2006, 290, H1289–H1297. [Google Scholar] [CrossRef] [PubMed]
- Wu, J.; Song, Y.; Li, H.; Chen, J. Rhabdomyolysis associated with fibrate therapy: Review of 76 published cases and a new case report. Eur. J. Clin. Pharmacol. 2009, 65, 1169–1174. [Google Scholar] [CrossRef] [PubMed]
- Lebrasseur, N.K.; Duhaney, T.A.; De Silva, D.S.; Cui, L.; Ip, P.C.; Joseph, L.; Sam, F. Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. Hypertension 2007, 50, 489–496. [Google Scholar] [CrossRef] [PubMed]
- Brigadeau, F.; Gele, P.; Wibaux, M.; Marquie, C.; Martin-Nizard, F.; Torpier, G.; Fruchart, J.C.; Staels, B.; Duriez, P.; Lacroix, D. The PPARalpha activator fenofibrate slows down the progression of the left ventricular dysfunction in porcine tachycardia-induced cardiomyopathy. J. Cardiovasc. Pharmacol. 2007, 49, 408–415. [Google Scholar] [CrossRef] [PubMed]
- Labinskyy, V.; Bellomo, M.; Chandler, M.P.; Young, M.E.; Lionetti, V.; Qanud, K.; Bigazzi, F.; Sampietro, T.; Stanley, W.C.; Recchia, F.A. Chronic activation of peroxisome proliferator-activated receptor-alpha with fenofibrate prevents alterations in cardiac metabolic phenotype without changing the onset of decompensation in pacing-induced heart failure. J. Pharmacol. Exp. Ther. 2007, 321, 165–171. [Google Scholar] [CrossRef] [PubMed]
- Ichihara, S.; Obata, K.; Yamada, Y.; Nagata, K.; Noda, A.; Ichihara, G.; Yamada, A.; Kato, T.; Izawa, H.; Murohara, T.; et al. Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors. J. Mol. Cell. Cardiol. 2006, 41, 318–329. [Google Scholar] [CrossRef] [PubMed]
- Ogata, T.; Miyauchi, T.; Sakai, S.; Irukayama-Tomobe, Y.; Goto, K.; Yamaguchi, I. Stimulation of peroxisome-proliferator-activated receptor alpha (PPAR alpha) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts. Clin. Sci. (Lond.) 2002, 103 (Suppl. 48), 284S–288S. [Google Scholar] [CrossRef] [PubMed]
- Duhaney, T.A.; Cui, L.; Rude, M.K.; Lebrasseur, N.K.; Ngoy, S.; De Silva, D.S.; Siwik, D.A.; Liao, R.; Sam, F. Peroxisome proliferator-activated receptor alpha-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload. Hypertension 2007, 49, 1084–1094. [Google Scholar] [CrossRef] [PubMed]
- Hafstad, A.D.; Khalid, A.M.; Hagve, M.; Lund, T.; Larsen, T.S.; Severson, D.L.; Clarke, K.; Berge, R.K.; Aasum, E. Cardiac peroxisome proliferator-activated receptor-alpha activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss. Cardiovasc. Res. 2009, 83, 519–526. [Google Scholar] [CrossRef] [PubMed]
- Linz, W.; Wohlfart, P.; Baader, M.; Breitschopf, K.; Falk, E.; Schafer, H.L.; Gerl, M.; Kramer, W.; Rutten, H. The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats. Acta Pharmacol. Sin. 2009, 30, 935–946. [Google Scholar] [CrossRef] [PubMed]
- Schafer, H.L.; Linz, W.; Falk, E.; Glien, M.; Glombik, H.; Korn, M.; Wendler, W.; Herling, A.W.; Rutten, H. AVE8134, a novel potent PPARalpha agonist, improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats. Acta Pharmacol. Sin. 2012, 33, 82–90. [Google Scholar] [CrossRef] [PubMed]
- Forman, B.M.; Chen, J.; Evans, R.M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. USA 1997, 94, 4312–4317. [Google Scholar] [CrossRef] [PubMed]
- Lam, V.H.; Zhang, L.; Huqi, A.; Fukushima, A.; Tanner, B.A.; Onay-Besikci, A.; Keung, W.; Kantor, P.F.; Jaswal, J.S.; Rebeyka, I.M.; et al. Activating PPARalpha Prevents Post-Ischemic Contractile Dysfunction in Hypertrophied Neonatal Hearts. Circ. Res. 2015. [Google Scholar] [CrossRef] [PubMed]
- Kliewer, S.A.; Sundseth, S.S.; Jones, S.A.; Brown, P.J.; Wisely, G.B.; Koble, C.S.; Devchand, P.; Wahli, W.; Willson, T.M.; Lenhard, J.M.; et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA 1997, 94, 4318–4323. [Google Scholar] [CrossRef] [PubMed]
- Brown, P.J.; Winegar, D.A.; Plunket, K.D.; Moore, L.B.; Lewis, M.C.; Wilson, J.G.; Sundseth, S.S.; Koble, C.S.; Wu, Z.; Chapman, J.M.; et al. A ureido-thioisobutyric acid (GW9578) is a subtype-selective PPARalpha agonist with potent lipid-lowering activity. J. Med. Chem. 1999, 42, 3785–3788. [Google Scholar] [CrossRef] [PubMed]
- Olsson, A.G.; Lang, P.D. One-year study of the effect of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinaemia. Atherosclerosis 1978, 31, 429–433. [Google Scholar] [CrossRef]
- Jonkers, I.J.; de Man, F.H.; van der Laarse, A.; Frolich, M.; Gevers Leuven, J.A.; Kamper, A.M.; Blauw, G.J.; Smelt, A.H. Bezafibrate reduces heart rate and blood pressure in patients with hypertriglyceridemia. J. Hypertens. 2001, 19, 749–755. [Google Scholar] [CrossRef] [PubMed]
- Peters, J.M.; Aoyama, T.; Burns, A.M.; Gonzalez, F.J. Bezafibrate is a dual ligand for PPARalpha and PPARbeta: Studies using null mice. Biochim. Biophys. Acta 2003, 1632, 80–89. [Google Scholar] [CrossRef]
- Yamaguchi, S.; Li, H.; Purevsuren, J.; Yamada, K.; Furui, M.; Takahashi, T.; Mushimoto, Y.; Kobayashi, H.; Hasegawa, Y.; Taketani, T.; et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: Evaluation by in vitro probe acylcarnitine assay. Mol. Genet. Metab. 2012, 107, 87–91. [Google Scholar] [CrossRef] [PubMed]
- Orngreen, M.C.; Madsen, K.L.; Preisler, N.; Andersen, G.; Vissing, J.; Laforet, P. Bezafibrate in skeletal muscle fatty acid oxidation disorders: A randomized clinical trial. Neurology 2014, 82, 607–613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dillon, L.M.; Hida, A.; Garcia, S.; Prolla, T.A.; Moraes, C.T. Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse. PLoS ONE 2012, 7, e44335. [Google Scholar] [CrossRef] [PubMed]
- Dumont, M.; Stack, C.; Elipenahli, C.; Jainuddin, S.; Gerges, M.; Starkova, N.; Calingasan, N.Y.; Yang, L.; Tampellini, D.; Starkov, A.A.; et al. Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice. Hum. Mol. Genet. 2012, 21, 5091–5105. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, Y.; Powers, C.; Moore, V.; Schafer, C.; Ren, M.; Phoon, C.K.; James, J.F.; Glukhov, A.V.; Javadov, S.; Vaz, F.M.; et al. The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome. Orphanet J. Rare Dis. 2017, 12, 49. [Google Scholar] [CrossRef] [PubMed]
- Djouadi, F.; Bastin, J. PPARs as therapeutic targets for correction of inborn mitochondrial fatty acid oxidation disorders. J. Inherit. Metab. Dis. 2008, 31, 217–225. [Google Scholar] [CrossRef] [PubMed]
- Nakajima, T.; Tanaka, N.; Kanbe, H.; Hara, A.; Kamijo, Y.; Zhang, X.; Gonzalez, F.J.; Aoyama, T. Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in mice: A novel peroxisome proliferator-activated receptor alpha-independent mechanism. Mol. Pharmacol. 2009, 75, 782–792. [Google Scholar] [CrossRef] [PubMed]
- Viscomi, C.; Bottani, E.; Civiletto, G.; Cerutti, R.; Moggio, M.; Fagiolari, G.; Schon, E.A.; Lamperti, C.; Zeviani, M. In vivo correction of COX deficiency by activation of the AMPK/PGC-1alpha axis. Cell Metab. 2011, 14, 80–90. [Google Scholar] [CrossRef] [PubMed]
- Johri, A.; Calingasan, N.Y.; Hennessey, T.M.; Sharma, A.; Yang, L.; Wille, E.; Chandra, A.; Beal, M.F. Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum. Mol. Genet. 2012, 21, 1124–1137. [Google Scholar] [CrossRef] [PubMed]
- Sugihara, J.; Imamura, T.; Nagafuchi, S.; Bonaventura, J.; Bonaventura, C.; Cashon, R. Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings. J. Clin. Investig. 1985, 76, 1169–1173. [Google Scholar] [CrossRef] [PubMed]
- Shibayama, N.; Miura, S.; Tame, J.R.; Yonetani, T.; Park, S.Y. Crystal structure of horse carbonmonoxyhemoglobin-bezafibrate complex at 1.55-A resolution. A novel allosteric binding site in R-state hemoglobin. J. Biol. Chem. 2002, 277, 38791–38796. [Google Scholar] [CrossRef] [PubMed]
- Schafer, C.; Moore, V.; Dasgupta, N.; Javadov, S.; James, J.F.; Glukhov, A.I.; Strauss, A.W.; Khuchua, Z. The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice. Front. Pharmacol. 2018, 9, 318. [Google Scholar] [CrossRef] [PubMed]
- Jakob, T.; Nordmann, A.J.; Schandelmaier, S.; Ferreira-Gonzalez, I.; Briel, M. Fibrates for primary prevention of cardiovascular disease events. Cochrane Database Syst. Rev. 2016, 11, CD009753. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Liu, B.; Tao, W.; Hao, Z.; Liu, M. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst. Rev. 2015, CD009580. [Google Scholar] [CrossRef] [PubMed]
- Goldenberg, I.; Benderly, M.; Goldbourt, U. Secondary prevention with bezafibrate therapy for the treatment of dyslipidemia: An extended follow-up of the BIP trial. J. Am. Coll. Cardiol. 2008, 51, 459–465. [Google Scholar] [CrossRef] [PubMed]
- Goldenberg, I.; Boyko, V.; Tennenbaum, A.; Tanne, D.; Behar, S.; Guetta, V. Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate: 16-year mortality follow-up of the bezafibrate infarction prevention trial. Arch. Intern. Med. 2009, 169, 508–514. [Google Scholar] [CrossRef] [PubMed]
- Goldenberg, I.; Benderly, M.; Sidi, R.; Boyko, V.; Tenenbaum, A.; Tanne, D.; Behar, S. Relation of clinical benefit of raising high-density lipoprotein cholesterol to serum levels of low-density lipoprotein cholesterol in patients with coronary heart disease (from the Bezafibrate Infarction Prevention Trial). Am. J. Cardiol. 2009, 103, 41–45. [Google Scholar] [CrossRef] [PubMed]
- Arbel, Y.; Klempfner, R.; Erez, A.; Goldenberg, I.; Benzekry, S.; Shlomo, N.; Fisman, E.Z.; Tenenbaum, A. Bezafibrate for the treatment of dyslipidemia in patients with coronary artery disease: 20-year mortality follow-up of the BIP randomized control trial. Cardiovasc. Diabetol. 2016, 15, 11. [Google Scholar] [CrossRef] [PubMed]
- Meade, T.; Zuhrie, R.; Cook, C.; Cooper, J. Bezafibrate in men with lower extremity arterial disease: Randomised controlled trial. BMJ 2002, 325, 1139. [Google Scholar] [CrossRef] [PubMed]
- Tenenbaum, A.; Motro, M.; Fisman, E.Z.; Tanne, D.; Boyko, V.; Behar, S. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch. Intern. Med. 2005, 165, 1154–1160. [Google Scholar] [CrossRef] [PubMed]
- Corpechot, C.; Chazouilleres, O.; Rousseau, A.; Le Gruyer, A.; Habersetzer, F.; Mathurin, P.; Goria, O.; Potier, P.; Minello, A.; Silvain, C.; et al. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N. Engl. J. Med. 2018, 378, 2171–2181. [Google Scholar] [CrossRef] [PubMed]
- Bonnefont, J.P.; Bastin, J.; Laforet, P.; Aubey, F.; Mogenet, A.; Romano, S.; Ricquier, D.; Gobin-Limballe, S.; Vassault, A.; Behin, A.; et al. Long-term follow-up of bezafibrate treatment in patients with the myopathic form of carnitine palmitoyltransferase 2 deficiency. Clin. Pharmacol. Ther. 2010, 88, 101–108. [Google Scholar] [CrossRef] [PubMed]
- Bastin, J.; Bonnefont, J.P.; Djouadi, F.; Bresson, J.L. Should the beneficial impact of bezafibrate on fatty acid oxidation disorders be questioned? J. Inherit. Metab. Dis. 2014, 38, 371–372. [Google Scholar] [CrossRef] [PubMed]
- Gobin-Limballe, S.; McAndrew, R.P.; Djouadi, F.; Kim, J.J.; Bastin, J. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim. Biophys. Acta 2010, 1802, 478–484. [Google Scholar] [CrossRef] [PubMed]
Disease Model | Tissue Studied | BF Dose | Effects | Ref. |
---|---|---|---|---|
OXPHOS defect: Surf1−/− | Muscle | 0.5% (0.6–0.8 g/kg) | Weight loss, hepatomegaly. Increased expression of FAO genes, PPARα and PPARβ/δ. | [98] |
OXPHOS defect: Cox15−/− | Muscle | 0.5% (0.6–0.8 g/kg) | Toxic, mitochondrial myopathy, excessive apoptosis. | [98] |
Huntington disease: Htt-ex1 (R6/2) | Brain, Muscle, BAT | 0.5% (0.6–0.8 g/kg) | Attenuated neurodegeneration in brain, prevented muscle–type switching. Increased exercise capacity and muscle strength, increased vacuolization in BAT, and extend survival. | [99] |
Premature aging: mtDNA polymerase γ−/− | Skin, Spleen | 0.5% (0.6–0.8 g/kg) | Delayed hair loss and restored skin structure. Improved spleen size and structure. | [93] |
BTHS: TAZ knockdown | Heart | 0.5% (0.6–0.8 g/kg) | Preserved cardiac systolic function. Reduced cardiolipin level in mitochondria. | [95] |
BTHS: TAZ knockdown | Heart, Muscle | 0.05% (0.06–0.08 g/kg) | Restored cardiac systolic function. Ameliorated exercise intolerance phenotype when treatment was combined with everyday voluntary exercise. | [102] |
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Khuchua, Z.; Glukhov, A.I.; Strauss, A.W.; Javadov, S. Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases. Int. J. Mol. Sci. 2018, 19, 3464. https://doi.org/10.3390/ijms19113464
Khuchua Z, Glukhov AI, Strauss AW, Javadov S. Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases. International Journal of Molecular Sciences. 2018; 19(11):3464. https://doi.org/10.3390/ijms19113464
Chicago/Turabian StyleKhuchua, Zaza, Aleksandr I. Glukhov, Arnold W. Strauss, and Sabzali Javadov. 2018. "Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases" International Journal of Molecular Sciences 19, no. 11: 3464. https://doi.org/10.3390/ijms19113464