Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2017-06-01
Date Acceptance
2017-03-23
Citation
Cardiovascular Research, 2017, 113 (7), pp.737-748
ISSN
0008-6363
Publisher
Oxford University Press (OUP)
Start Page
737
End Page
748
Journal / Book Title
Cardiovascular Research
Volume
113
Issue
7
Copyright Statement
© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), whichpermits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use,please contactjournals.permissions@oup.com
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/28419197
PII: 3737832
Subjects
Energy
Fatty acid
Glucose
Hypoxia
Metabolism
Animals
CD36 Antigens
Cell Hypoxia
Citric Acid Cycle
Diabetes Mellitus, Type 2
Diabetic Cardiomyopathies
Energy Metabolism
Fatty Acids
Isolated Heart Preparation
Lipid Metabolism
Male
Myocardial Reperfusion Injury
Myocardium
Oleic Acids
Oxidation-Reduction
Oxidative Stress
Rats, Wistar
Sarcolemma
Succinimides
Time Factors
Triglycerides
Ventricular Function, Left
Ventricular Pressure
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2017-04-17