The effects of ginsenoside Rb1 on fatty acid β-oxidation, mediated by AMPK, in the failing heart

Document Type: Original Article

Authors

1 Department of Cardiology, the People’s Hospital of Liaoning Province, i.e. the People’s Hospital of China Medical University, Shenyang, China

2 Clinical Ophthalmology, the First Affiliated Hospital, China Medical University, Shenyang, China

3 Dalian Medical University, Dalian, China

Abstract

Objective(s): This study intended to investigate the effects of Ginsenoside-Rbl (Gs-Rbl) on fatty acid β-oxidation (FAO) in rat failing heart and to identify potential mechanisms of Gs-Rbl improving heart failure (HF) by FAO pathway dependent on AMP-activated protein kinase (AMPK).
Materials and Methods: Rats with chronic HF, induced by adriamycin (Adr), were randomly grouped into 7 groups. Gs-Rb1, adenine 9-β-D-arabinofuranoside (Ara A, specific AMPK inhibitor), and 5'-aminoimidazole-4-carboxamide riboside (Aicar, specific AMPK activator) were administered to rats with HF, singly and/or combinedly. Myocardial high-energy phosphate (such as phosphocreatine, ADP, and ATP), free L-Carnitine, malonyl-CoA, and the activity of FAO-related enzymes in left ventricle from different groups were measured by using the corresponding molecular biological techniques.
Results: Gs-Rb1 improved HF significantly, accompanied by a significant increase in phosphocreatine (PCr), ADP, ATP, PCr/ATP ratio, free carnitine, malonyl-CoA, mRNA, activity of carnitine palmitoyltransferase (Cpt), medium-chain Acyl-CoA Dehydrogenase (MCAD) and long-chain acyl-CoA Synthetase (ACSL) and a significant decrease of the ADP/ATP ratio in the left ventricular myocardium. However, all those effects were almost abolished by Ara A and were not further improved by Aicar.
Conclusion: Taken together, it suggests that Gs-Rb1 may modulate cardiac metabolic remodeling by improving myocardial fatty acid β-oxidation in failing heart. In addition, the effects of Gs-Rb1 may be mediated via activating AMPK.

Keywords

Main Subjects


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Dyck JR, Cheng JF, Stanley WC, Barr R, Chandler MP, Brown S, et al. Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ Res. 2004;94:e78–e84.
Dyck JR, Hopkins TA, Bonnet S, Michelakis ED, Young ME, Watanabe M, et al. Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation. 2006;114:1721–1728.
Beshay NM Zordoky, Jeevan Nagendran, Thomas Pulinilkunnil, Petra C Kienesberger, Grant Masson, Terri J Waller, et al. AMPK-Dependent Inhibitory Phosphorylation of ACC Is Not Essential for Maintaining Myocardial Fatty Acid Oxidation. Circ Res. 2014;115:518-524.
Lei B, Lionetti V, Young ME, Chandler MP, d’ Agostino C, Kang E, et al. Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J Mol Cell Cardiol. 2004;36: 567–576.  
Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation. 1996;94: 2837–2842.
Martin MA, Gomez MA, Guillen F, Bornstein B, Campos Y, Rubio JC, et al. Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure. Biochim Biophys Acta. 2000;1502: 330–336.
Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C, et al. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2007;293: H3270–3278.
Yazaki Y, Isobe M, Takahashi W, Kitabayashi H, Nishiyama O, Sekiguchi M, et al. Assessment of myocardial fatty acid metabolic abnormalities in patients with idiopathic dilated cardiomyopathy using 123I BMIPP SPECT: correlation with clinicopathological findings and clinical course. Heart. 1999;81: 153–159.
Marie A. Schroeder,  Angus Z Lau, Albert P Chen, Yiping Gu, Jeevan Nagendran, et al. Hyperpolarized 13C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart. Eur J Heart Fail. 2013; 15: 130–140.
Lionetti V, Linke A, Chandler MP, Young ME, Penn MS, Gupte S, et al. Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure. Cardiovasc Res. 2005;66: 274–281.
Heather LC, Cole MA, Lygate CA, Evans RD, Stuckey DJ, Murray AJ, et al. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc Res. 2006; 72: 430-437.