Abstract
Background: Endothelial dysfunction plays a critical role in the pathogenesis of diabetic complications. Diabetes-mediated reactive aldehydes like 4-hydroxy-2-nonenal (4HNE) are associated with endothelial cell impairment. Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme which detoxifies 4HNE, protects heart function against diabetic cardiomyopathy. Nearly 600 million East Asians have a point mutation of ALDH2, termed as ALDH2*2, which causes an intrinsic low ALDH2 activity. Previously, we reported an aggravated coronary endothelial dysfunction in ALDH2*2 mutant knock-in mice (ALDH2*2 mice) with diabetes. Aldehyde dehydrogenase activator 1 (Alda-1) is the only known activator for both normal ALDH2 and mutant ALDH2*2. We hypothesized that Alda-1 could protect endothelial cells (ECs) from hyperglycemia induced coronary endothelial dysfunction in diabetic ALDH2*2 mice. Methods and Results: Diabetes was induced by streptozotocin injection (150 mg/kg) to ALDH2*2 mice. Alda-1 (10 mg/kg/d, DM-A) or vehicle (DM-V) was delivered through mini-pumps for 3 weeks after diabetes. We found an increased left ventricular pressure (59.9±18.7 vs 66.4±20.1 mmHg) and a decreased perfusion pressure (89.4±8.1 vs 83.6±12.1 mmHg) in Langendorff hearts from DM-A (DM-V vs DM-A, p<0.05, respectively). In heart sections, CD31+ (127.2±22.3 vs 270.5±53.7 /mm 2 ) and eNOS+ cells (136.2±22.8 vs 366.7±33.6 /mm 2 ) were increased while apoptosis (1117.5±303.6 vs 727.1±254.8 /mm 2 ) and 4HNE+ (515.8±8.3 vs 181.7±72.5 /mm 2 ) cells were reduced in DM-A (DM-V vs DM-A, p<0.05, respectively). Direct perfusion of 4HNE to Langendorff hearts from control ALDH2*2 mice (4HNE) increased perfusion pressure (Δ3.18±0.5 vs Δ36.6±7.7 mmHg), arteriole closure (8.3±0.4 vs 39.8±3.7 /mm 2 ), and decreased eNOS+ cells (2877.1±117.3 vs 37.5±5.6 /mm 2 ) (Sham vs 4HNE, p<0.05). One-day Alda-1 (10 mg/kg) pre-treatment before 4HNE perfusion (A-4HNE) decreased perfusion pressure (Δ7.1±1.7 mmHg), number of closed arterioles (22.4±4.8 /mm 2 ), and increased eNOS+ (878.0±121.3 /mm 2 ) cells (4HNE vs A-4HNE, p<0.05, respectively). Conclusion: Alda-1 protects hyperglycemia mediated 4HNE induced coronary endothelial dysfunction and thereby cardiac tissue in ALDH2*2 diabetic mice.
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