Effect of chronic CPT-1 inhibition on myocardial ischemia-reperfusion injury (I/R) in a model of diet-induced obesity

Cardiovasc Drugs Ther. 2012 Jun;26(3):205-16. doi: 10.1007/s10557-012-6377-1.

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors*
  • Diet
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Heart / physiopathology
  • Male
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology*
  • Myocardial Reperfusion Injury
  • Obesity / pathology
  • Obesity / physiopathology*
  • Rats
  • Rats, Wistar

Substances

  • Enzyme Inhibitors
  • 4-hydroxyphenylglycine
  • Carnitine O-Palmitoyltransferase
  • Glycine