Diabetes mellitus (DM) afflicts 26 million people in the US. Around 65% of these diabetic patients die of cardiovascular complications. We and others have found that DM increases reactive oxygen species (ROS)- mediated aldehydes like 4-hydroxy-2-nonenal (4HNE) levels. 4HNE forms covalent bonds with macromolecules known as adducts, which lead to cellular damage and decreased cardiac function. Aldehyde dehydrogenase (ALDH2) is a cardiac mitochondrial enzyme that detoxifies 4HNE greatly in the heart. We and others have reported that in streptozotocin-induced hyperglycemic models increase in 4HNE protein adducts and decrease in myocardial ALDH2 activity correlate with cardiomyopathy. Although we think this causes cardiac dysfunction, the exact mechanism is unclear. However, most diabetic patients have type-2 DM. Thus, it is imperative to investigate whether increased mitochondrial 4HNE and lower ALDH2 activity in the cardiomyocytes contribute to cardiac dysfunction in type-2 DM models. We recently demonstrated that high glucose stress or 4HNE administration decreased mitochondrial respiration with increased mitochondrial DNA (mtDNA) damage in cultured cardiomyocytes. In our preliminary study using type-2 diabetic mouse heart, we found an increase in mitochondrial levels of 8-hydroxyguanine (8OHG), an oxidized mtDNA product, which is primarily repaired by 8- oxoguanine glycosylase (OGG)-1. Next, we found increased 4HNE adduct formation on OGG-1 and reduced cardiac OGG-1 levels. These data suggest that 4HNE adduction on OGG-1 reduces its level and activity thereby raising the unmetabolized 8OHG level. Thus, we postulate that 4HNE-mediated mtDNA damage is part of the mechanism by which lower ALDH2 causes mitochondrial respiratory dysfunction and thus cardiac contractile dysfunction. To test our idea, we will use a high-fat diet induced type-2 DM model in wild type C57BL/6 and ALDH2*2 mutant mice. This mutation mimics East Asians with the E487K variant (ALDH2*2), which exhibits lower ALDH2 activity. We will overexpress ALDH2 and OGG-1 genes in the myocardium in situ or treat our diabetic mice with Alda-1, the only specific drug available to improve the catalytic activity of both wild type and mutant ALDH2. We propose following two specific aims:
Aim 1. To determine whether increased 4HNE adduction on mtOGG-1 causes mtDNA damage, poor mitochondrial respiration, and impaired cardiomyocyte contractility in type-2 DM.
Aim 2. To determine whether decreasing 4HNE-mediated mtDNA damage after the onset of cardiac dysfunction in type2-DM attenuates pathogenesis of cardiomyopathy. This study will identify a novel role of ALDH2 in type-2 DM mediated cardiac dysfunction and establish that ALDH2 could be a therapeutic target for restoring cardiac function in type-2 diabetic patients.