Modulation of fatty acid metabolism is involved in the alleviation of isoproterenol-induced rat heart failure by fenofibrate

Li,Ping; Luo,Shike; Pan,Chunji; Cheng,Xiaoshu

doi:10.3892/mmr.2015.4466

Modulation of fatty acid metabolism is involved in the alleviation of isoproterenol-induced rat heart failure by fenofibrate

Authors:
- Ping Li
- Shike Luo
- Chunji Pan
- Xiaoshu Cheng
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Affiliations: Department of Cardiovascular Medicine, The 2nd Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Cardiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
Published online on: October 21, 2015 https://doi.org/10.3892/mmr.2015.4466
Pages: 7899-7906
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Heart failure is a disease predominantly caused by an energy metabolic disorder in cardiomyocytes. The present study investigated the inhibitory effects of fenofibrate (FF) on isoproterenol (ISO)‑induced hear failure in rats, and examined the underlying mechanisms. The rats were divided into CON, ISO (HF model), FF and FF+ISO (HF animals pretreated with FF) groups. The cardiac structure and function of the rats were assessed, and contents of free fatty acids and glucose metabolic products were determined. In addition, myocardial cells were isolated from neonatal rats and used in vitro to investigate the mechanisms by which FF relieves heart failure. Western blot analysis was performed to quantify the expression levels of peroxisome proliferator‑activated receptor (PPAR)α and uncoupling protein 2 (UCP2). FF effectively alleviated the ISO‑induced cardiac structural damage, functional decline, and fatty acid and carbohydrate metabolic abnormalities. Compared with the ISO group, the serum levels of brain natriuretic peptide (BNP), free fatty acids, lactic acid and pyruvic acid were decreased in the FF animals. In the cultured myocardial cells, lactic acid and pyruvic acid contents were lower in the supernatants obtained from the FF animals, with lower levels of mitochondrial ROS production and cell necrosis, compared with the ISO group, whereas PPARα upregulation and UCP2 downregulation occurred in the FF+ISO group. The results demonstrated that FF efficiently alleviated heart failure in the ISO‑induced rat model, possibly via promoting fatty acid oxidation.

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1	Stewart S, MacIntyre K, Capewell S and McMurray JJ: Heart failure and the aging population: An increasing burden in the 21st century? Heart. 89:49–53. 2003. View Article : Google Scholar
2	Bettari L, Fiuzat M, Felker GM and O'Connor CM: Significance of hyponatremia in heart failure. Heart Fail Rev. 17:17–26. 2012. View Article : Google Scholar
3	Dayer M and Cowie MR: Heart failure: Diagnosis and healthcare burden. Clin Med. 4:13–18. 2004. View Article : Google Scholar : PubMed/NCBI
4	Sinatra ST: Metabolic cardiology: The missing link in cardiovascular disease. Altern Ther Health Med. 15:48–50. 2009.PubMed/NCBI
5	Herrmann G and G D: The chemical nature of heart failure. Ann Intern Med. 12:1233–1244. 1939. View Article : Google Scholar
6	Neubauer S: The failing heart-an engine out of fuel. N Engl J Med. 356:1140–1151. 2007. View Article : Google Scholar : PubMed/NCBI
7	J I: ATP and the heart [M]. Kluwer academic publishers USA; pp. 197–216. 2002
8	Nagoshi T, Yoshimura M, Rosano GMC, Lopaschuk GD and Mochizuki S: Optimization of cardiac metabolism in heart failure. Curr Pharm Des. 17:3846–3853. 2011. View Article : Google Scholar : PubMed/NCBI
9	Kim T and Yang Q: Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system. World J Cardiol. 5:164–174. 2013. View Article : Google Scholar : PubMed/NCBI
10	Planavila A, Rodriguez-Calvo R, Jové M, Michalik L, Wahli W, Laguna JC and Vázquez-Carrera M: Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes. Cardiovasc Res. 65:832–841. 2005. View Article : Google Scholar : PubMed/NCBI
11	Umemoto T and Fujiki Y: Ligand-dependent nucleo-cytoplasmic shuttling of peroxisome proliferator-activated receptors, PPAR α and PPAR γ. Genes Cells. 17:576–596. 2012. View Article : Google Scholar : PubMed/NCBI
12	Scott R, O'Brien R, Fulcher G, Pardy C, D'Emden M, Tse D, Taskinen MR, Ehnholm C and Keech A; Fenofibrate Intervention Event Lowering in Diabetes (FIELD) Study Investigators: Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: The fenofibrate intervention and event lowering in diabetes (FIELD) study. Diabetes Care. 32:493–498. 2009. View Article : Google Scholar :
13	Teshima Y, Akao M, Jones SP and Marbán E: Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res. 93:192–200. 2003. View Article : Google Scholar : PubMed/NCBI
14	Echtay KS: Mitochondrial uncoupling proteins - what is their physiological role? Free Radic Biol Med. 43:1351–1371. 2007. View Article : Google Scholar : PubMed/NCBI
15	Deng S, Yang Y, Han Y, Li X, Wang X, Zhang Z and Wang Y: UCP2 inhibits ROS-mediated apoptosis in A549 under hypoxic conditions. PLoS One. 7:e307142012. View Article : Google Scholar : PubMed/NCBI
16	Ingwall JS: Energy metabolism in heart failure and remodelling. Cardiovasc Res. 81:412–419. 2009. View Article : Google Scholar :
17	Askoxylakis V, Thieke C, Pleger ST, Most P, Tanner J, Lindel K, Katus HA, Debus J and Bischof M: Long-term survival of cancer patients compared to heart failure and stroke: A systematic review. BMC Cancer. 10(105)2010. View Article : Google Scholar : PubMed/NCBI
18	Joiner ML, Koval OM, Li J, He BJ, Allamargot C, Gao Z, Luczak ED, Hall DD, Fink BD, Chen B, et al: CaMKII determines mitochondrial stress responses in heart. Nature. 491:269–273. 2012. View Article : Google Scholar : PubMed/NCBI
19	Andalib S, Shayanfar A, Khorrami A, Maleki-Dijazi N and Garjani A: Atorvastatin reduces the myocardial content of coenzyme Q10 in isoproterenol-induced heart failure in rats. Drug Res (Stuttg). 64:246–250. 2014.
20	Heymes C, Bendall JK, Ratajczak P, Cave AC, Samuel JL, Hasenfuss G and Shah AM: Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol. 41:2164–2171. 2003. View Article : Google Scholar : PubMed/NCBI
21	Burkart EM, Sambandam N, Han X, Gross RW, Courtois M, Gierasch CM, Shoghi K, Welch MJ and Kelly DP: Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest. 117:3930–3939. 2007.PubMed/NCBI
22	Wolins NE, Quaynor BK, Skinner JR, Tzekov A, Croce MA, Gropler MC, Varma V, Yao-Borengasser A, Rasouli N, Kern PA, et al: OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization. Diabetes. 55:3418–3428. 2006. View Article : Google Scholar : PubMed/NCBI
23	Sack MN, Rader TA, Park S, Bastin J, McCune SA and Kelly DP: Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation. 94:2837–2842. 1996. View Article : Google Scholar : PubMed/NCBI
24	Garnier A, Fortin D, Deloménie C, Momken I, Veksler V and Ventura-Clapier R: Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol. 551:491–501. 2003. View Article : Google Scholar : PubMed/NCBI
25	Murray AJ, Anderson RE, Watson GC, Radda GK and Clarke K: Uncoupling proteins in human heart. Lancet. 364:1786–1788. 2004. View Article : Google Scholar : PubMed/NCBI
26	Noma T, Nishiyama A, Mizushige K, Murakami K, Tsuji T, Kohno M, Rahman M, Fukui T, Abe Y and Kimura S: Possible role of uncoupling protein in regulation of myocardial energy metabolism in aortic regurgitation model rats. FASEB J. 15:1206–1208. 2001.PubMed/NCBI
27	Young ME, Patil S, Ying J, Depre C, Ahuja HS, Shipley GL, Stepkowski SM, Davies PJ and Taegtmeyer H: Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J. 15:833–845. 2001. View Article : Google Scholar : PubMed/NCBI
28	Li P, Yin K, Luo SK and Cheng XS: Effect of uncoupling protein-2 on angiotensin II induced reactive oxygen species generation in mitochondria. Chinese Journal of Hypertension. 18:940–945. 2010.In Chinese.
29	Luo SK, Li P and Cheng XS: Establishment of model of isoprenaline-induced chronic heart failure in rats. Chongqing Yixue. 41:352–354. 2012.