Effect of Chronic CPT-1 Inhibition on Myocardial Ischemia-Reperfusion Injury (I/R) in a Model of Diet-Induced Obesity
- 320 Downloads
By increasing circulating free fatty acids and the rate of fatty acid oxidation, obesity decreases glucose oxidation and myocardial tolerance to ischemia. Partial inhibition of fatty acid oxidation may improve myocardial tolerance to ischemia/reperfusion (I/R) in obesity. We assessed the effects of oxfenicine treatment on post ischemic cardiac function and myocardial infarct size in obese rats.
Male Wistar rats were fed a control diet or a high calorie diet which resulted in diet induced obesity (DIO) for 16 weeks. Oxfenicine (200 mg/kg/day) was administered to control and DIO rats for the last 8 weeks. Isolated hearts were perfused and infarct size and post ischemic cardiac function was assessed after regional or global ischemia and reperfusion. Cardiac mitochondrial function was assessed and myocardial expression and activity of CPT-1 (carnitine palmitoyl transferase-1) and IRS-1 (insulin receptor substrate-1) was assessed using Western blot analysis.
In the DIO rats, chronic oxfenicine treatment improved post ischemic cardiac function and reduced myocardial infarct size after I/R but had no effect on the cardiac mitochondrial respiration. Chronic oxfenicine treatment worsened post ischemic cardiac function, myocardial infarct size and basal mitochondrial respiration in control rat hearts. Basal respiratory control index (RCI) values, state 2 and state 4 respiration rates and ADP phosphorylation rates were compromised by oxfenicine treatment.
Chronic oxfenicine treatment improved myocardial tolerance to I/R in the obese rat hearts but decreased myocardial tolerance to I/R in control rat hearts. This decreased tolerance to ischemia of oxfenicine treated controls was associated with adverse changes in basal and reoxygenation mitochondrial function. These changes were absent in oxfenicine treated hearts from obese rats.
Key wordsOxfenicine Cardiac metabolism CPT-1 inhibition Obesity Ischemia/reperfusion
This study was financially supported by the South African National Research Foundation (Prof. E.F. Du Toit and Dr. E. Marais). We would also like to thank Prof. A. Lochner and Prof. B. Huisamen for expert advice and guidance.
Conflict of interest
- 2.Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation and effect of weight loss: an update of the 1997 American Heart Association scientific statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity and metabolism. Circulation. 2006;113:898–918.PubMedCrossRefGoogle Scholar
- 4.Kobayashi H, Nakamura T, Miyaoka K, Nishida M, Funahashi T, Yamashita S, et al. Visceral fat accumulation contributes to insulin resistance, small sized low-density lipoprotein and progression of coronary artery disease in middle-aged non-obese Japanese men. Jpn Circ J. 2001;65:193–9.PubMedCrossRefGoogle Scholar
- 9.Carley AN, Severson DL. Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim ET Biophys Acta. 2005;1734:112–26.Google Scholar
- 10.Opie LH. The heart: physiology and metabolism, second edition Raven Press 1991.Google Scholar
- 16.Rupp H, Zarain-Herzberg A, Maisch B. The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure. Urban Vogel. 2002;27:621–36.Google Scholar
- 26.Chang KC, Tseng CD, Lu SC, Liang JT, Wu MS, Tsai MS, et al. Effects of acetyl-L-carnitine and oxfenicine on aorta stiffness in diabetic rats. Eur J Clin Invest. 2010;40:1–9.Google Scholar
- 51.Barr RL, Lopaschuk GD. Direct measurement of energy metabolism in the isolated working rat heart. JPM. 1997;38:11–7.Google Scholar
- 52.Lochner A, Du Toit EF, Huisamen B, Koeslag JH, Moolman JA. Cellular injury in ischemia. Cardiovasc Journ of South Africa. 2004;15:205–6.Google Scholar
- 54.Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline in chronic heart failure a randomized, controlled trial of short-term use of a novel treatment. Circ Res. 2005;112:3280–8.Google Scholar
- 61.Bielefeld DR, Vary TC, Neely JR. Inhibition of Carnitine Palmitoyl-CoA Transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscle. Mol Cell Cardiol. 1985;17:619–25.Google Scholar