Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function

BMC Medicine

Jun Ren²  Haichang Wang¹  Jacalyn R Maris²  Nan Hu²  Sara A Babcock²  Yingmei Zhang² 

[1] Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China;Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA

关键词: mitochondrial function;    GSK3β;    diabetes;    cardiac contraction;    ALDH2;   

Others  :  1126262
DOI  :  10.1186/1741-7015-10-40

 received in 2012-01-18, accepted in 2012-04-23,  发布年份 2012

【 摘 要 】

Background

Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated.

Methods

This study was designed to evaluate the impact of ALDH2 on streptozotocin-induced diabetic cardiomyopathy. Friendly virus B(FVB) and ALDH2 transgenic mice were treated with streptozotocin (intraperitoneal injection of 200 mg/kg) to induce diabetes.

Results

Echocardiographic evaluation revealed reduced fractional shortening, increased end-systolic and -diastolic diameter, and decreased wall thickness in streptozotocin-treated FVB mice. Streptozotocin led to a reduced respiratory exchange ratio; myocardial apoptosis and mitochondrial damage; cardiomyocyte contractile and intracellular Ca²⁺ defects, including depressed peak shortening and maximal velocity of shortening and relengthening; prolonged duration of shortening and relengthening; and dampened intracellular Ca²⁺ rise and clearance. Western blot analysis revealed disrupted phosphorylation of Akt, glycogen synthase kinase-3β and Foxo3a (but not mammalian target of rapamycin), elevated PTEN phosphorylation and downregulated expression of mitochondrial proteins, peroxisome proliferator-activated receptor γ coactivator 1α and UCP-2. Intriguingly, ALDH2 attenuated or ablated streptozotocin-induced echocardiographic, mitochondrial, apoptotic and myocardial contractile and intracellular Ca²⁺ anomalies as well as changes in the phosphorylation of Akt, glycogen synthase kinase-3β, Foxo3a and phosphatase and tensin homologue on chromosome ten, despite persistent hyperglycemia and a low respiratory exchange ratio. In vitro data revealed that the ALDH2 activator Alda-1 and glycogen synthase kinase-3β inhibition protected against high glucose-induced mitochondrial and mechanical anomalies, the effect of which was cancelled by mitochondrial uncoupling.

Conclusions

In summary, our data revealed that ALDH2 acted against diabetes-induced cardiac contractile and intracellular Ca²⁺ dysregulation, possibly through regulation of apoptosis, glycogen synthase kinase-3β activation and mitochondrial function independent of the global metabolic profile.

【 授权许可】

   
2012 Zhang et al; licensee BioMed Central Ltd.

【 图 表 】

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