Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation.

Abstract

AIMS:

The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.

METHODS AND RESULTS:

Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels.

CONCLUSIONS:

Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.

• Authors: Latt S Mansor, Maria da Luz Sousa Fialho, Georgina Yea, Will A Coumans, James A West, Matthew Kerr, Carolyn A Carr, Joost J F P Luiken, Jan F C Glatz, Rhys D Evans, Julian L Griffin, Damian J Tyler, Kieran Clarke, Lisa C Heather
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 113 Issue 7 Pg. 737-748 (Jun 01 2017) ISSN: 1755-3245 [Electronic] England
• PMID: 28419197 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published on behalf of the European Society of Cardiology

Chemical References

• CD36 Antigens
• Cd36 protein, rat
• Fatty Acids
• Oleic Acids
• Succinimides
• Triglycerides
• sulfo-N-succinimidyl oleate

Topics

• Animals
• CD36 Antigens (antagonists & inhibitors, metabolism)
• Cell Hypoxia
• Citric Acid Cycle (drug effects)
• Diabetes Mellitus, Type 2 (complications, metabolism, physiopathology)
• Diabetic Cardiomyopathies (drug therapy, etiology, metabolism, physiopathology)
• Energy Metabolism (drug effects)
• Fatty Acids (metabolism)
• Isolated Heart Preparation
• Lipid Metabolism (drug effects)
• Male
• Myocardial Reperfusion Injury (drug therapy, etiology, metabolism, physiopathology)
• Myocardium (metabolism)
• Oleic Acids (pharmacology)
• Oxidation-Reduction
• Oxidative Stress (drug effects)
• Rats, Wistar
• Sarcolemma (drug effects, metabolism)
• Succinimides (pharmacology)
• Time Factors
• Triglycerides (metabolism)
• Ventricular Function, Left (drug effects)
• Ventricular Pressure (drug effects)