Gudong Pan, Mandar Deshpande, Vishal R. Mali, Jiang Xu, Xiao-Ping Yang and Suresh S. Palaniyandi
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA and Department of Physiology, Wayne State University, Detroit, MI, 48202, USA
A single-point mutation (E487K) in aldehyde dehydrogenase (ALDH) 2 (ALDH2*2) increases aldehyde toxicity in East Asians due to low intrinsic ALDH2 activity. Decreased ALDH2 activity is associated with cardiovascular diseases in humans and animal models. Our hypothesis is that low intrinsic 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). 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. 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. Mitochondrial respiration was reduced significantly 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. While 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. Increased mitochondrial DNA (mtDNA) damage and resultant decrease in MtDNA-encoded respiratory complex proteins were augmented 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.