Abstract 219: Diabetes-induced Mitochondrial Dna Damage and Cardiac Dysfunction are Aggravated Due to Low Aldehyde Dehydrogenase 2 (aldh2) Activity in Aldh 2*2 (e487k) Knock-in Mutant Mice

Abstract

A prevalent mutation (E487K) in aldehyde dehydrogenase (ALDH) 2, a cardiac mitochondrial enzyme, in East Asians (ALDH2*2) reduces ALDH2 activity and thereby increases aldehyde toxicity. Decreased ALDH2 activity is associated with cardiovascular diseases in humans and animal models. In this study, we hypothesized that reduction in ALDH2 activity in ALDH2*2 mice is sufficient to increase 4-hydroxy-2-nonenal (4HNE) levels and impair mitochondrial respiration and consequently induce cardiac damage in diabetes mellitus (DM). To test the hypothesis, streptozotocin (150 mg/kg i.p.) injected type-1 diabetic ALDH2*2 and C57BL mice as well as corresponding non-diabetic mice were employed. Four experimental groups were C57BL Control, C57BL DM, ALDH2*2 Control, and ALDH2*2 DM. N=6. Data were presented below in the same order. The mice were sacrificed after 3 weeks of DM. Myocardial ALDH2 activity and levels were reduced and 4HNE protein adducts were increased in ALDH2*2 DM mice relative to C57BL DM mice. Decrease in mitochondrial respiration was higher in ALDH2*2 DM mice compared to C57BL DM. Increase in cardiac hypertrophy (207 ± 8, 355 ± 4, 289 ± 22, 370 ± 20 in μm2; $$P<0.01 ALDH2*2 DM vs C57 DM) and fibrosis (4 ± 0.4, 8 ± 0.5, 6 ± 0.7, 9 ± 2.3 in % area of fibrosis; $$P<0.01 ALDH2*2 DM vs C57 DM) were higher in ALDH2*2 DM mice compared to C57BL DM. But the contractile function (56 ± 0.7, 54 ± 1.6, 43 ± 2.7, 48 ± 1.8 in %FS; $p <0.05 ALDH2*2 DM vs C57 DM) was lower only in ALDH2*2 DM, not WT DM. At the molecular level, increased mitochondrial DNA (mtDNA) damage and resultant decrease in MtDNA-encoded respiratory complex proteins were potentiated in diabetic ALDH2*2 mice compared to C57BL DM mice. Based on our data, we conclude that reduced ALDH2 activity in ALDH2*2 mice aggravated diabetes-induced cardiac mitochondrial respiratory dysfunction, ventricular remodeling and dysfunction.