Abstract 18067: Targeting Mitochondrial DNA to Reduce Consequences of Oxidative Stress: Role in the Prevention of the Diabetic Cardiomyopathy

Abstract

Mitochondrial dysfunction and increased oxidative stress are hallmarks of diabetic cardiomyopathy, a condition characterized by increased risk of heart failure, independent of coronary atherosclerosis. Mitochondria not only are the major site of energy production, but also generate reactive oxygen species (ROS), and metabolic signals that produce coronary metabolic vasodilation (coupling of flow to metabolism). Accordingly, we hypothesized that elevations in mitochondrial ROS in obesity and diabetes produce oxidative mitochondrial DNA (mtDNA) injury (fragmentation); thus by repairing mtDNA fragmentation, we would restore coronary metabolic dilation. To test this hypothesis, we studied Zucker fatty obese rats (ZOF), lean littermates (ZL), and ZOF in which mtDNA fragmentation was repaired by administration of a cell permeable recombinant protein containing endonucleaseIII and a mitochondrial localization sequence (mt-tat-ENDOIII), which repairs fragmented mtDNA and restores mitochondrial functions. ZOF were treated daily for 3 days (1 µg/g body weight of mt-tat-ENDOIII). ZOF and ZL rats treated with vehicle were positive and negative controls, respectively. The product of mean arterial pressure and heart rate was used as a surrogate of cardiac work (CW). Myocardial blood flow (MBF) was measured by contrast echocardiography under baseline conditions (hexamethonium) and during NE infusion (i.v. norepinephrine, NE) to increase CW. During metabolic stress, ZOF showed coronary insufficiency compared to ZL (P<0.05). Importantly, coronary metabolic dilation in ZOF was restored by the administration of mt-tat-ENDOIII versus ZL (P=NS). We conclude that mitochondrial dysfunction participates to decrease the efficiency of the coronary metabolic regulation in diabetes. By preventing mt-DNA damage, adequate coronary metabolic dilatation can be restored; this could be a therapeutic approach for the prevention of diabetic cardiomyopathy.