Abstract 16923: Oxidative Mitochondrial Dna Damage - A Potential Link Between Insulin Resistance and Heart Failure in Ageing Obese Mice

Introduction: Obesity and age play a central role in the development of insulin resistance, which is a crucial abnormality driving cardiovascular complications. Chronic diabetes can affect cardiac muscle directly, leading to a decline in cardiac function, known as “diabetic cardiomyopathy”. However, molecular mechanisms underlying the link between insulin resistance and heart failure are not clear. Hypothesis: Here, we hypothesize that oxidative mtDNA damage is a linking mechanism between insulin resistance and heart failure, since it contributes to all main pathways distinctive of both processes. Methods: In the present study we used 15-month old mice of three genotypes with different levels of mtDNA oxidation because of altered expression of DNA repair glycosylase Ogg1, the first enzyme in the base excision repair pathway in mitochondria. Wild type (WT) mice, Ogg1 knock-out (KO) mice and KO mice transgenically overexpressing mitochondria-targeted Ogg1 (KOTG) were fed a high fat diet for 14 weeks and analyzed for mtDNA damage, bioenergetic and cardiac functions, and blood glucose and insulin levels. Results: Our previous results showed that young mice deficient in Ogg1 had increased mtDNA damage, altered mitochondrial respiration and left ventricle hypertrophy, but, despite these abnormalities, their cardiac function remained unchanged. Echocardiography of ageing mice in the present study demonstrated increased left ventricle mass (1.5 fold, p<0.05) and decreased cardiac contractility in KO mice when compared to WT animals (ejection fraction: 54.2±3.1 vs. 71.9±5.2 %, respectively, p<0.05). Compared to hearts from WT mice, KO animals displayed a significant decrease in ATP levels (7.2±0.3 vs. 3.8±0.4 pmole/mcl respectively, p<0.05). These changes in cardiac function and bioenergetics observed in KO mice were accompanied by increase in blood glucose and insulin levels. Interestingly, young (5-month old) KO mice fed a high fat diet also demonstrated increased glucose (KO 256.7±19.9 vs. WT 180.8±22.8 mg/dl, p<0.05) and insulin (5 fold, p<0.05) levels when compared to WT animals. These observations indicate that KO mice fed a high fat diet may develop insulin resistance. All these changes were prevented in KOTG mice, which were not statistically different from WT animals. Conclusions: Our results suggest that oxidative mtDNA damage could be a converging point that links both insulin resistance and heart failure in aging obese mice.