%0 Journal Article
%T Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3¦Â and mitochondrial function
%A Yingmei Zhang
%A Sara A Babcock
%A Nan Hu
%A Jacalyn R Maris
%A Haichang Wang
%A Jun Ren
%J BMC Medicine
%D 2012
%I BioMed Central
%R 10.1186/1741-7015-10-40
%X 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.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-3¦Â and Foxo3a (but not mammalian target of rapamycin), elevated PTEN phosphorylation and downregulated expression of mitochondrial proteins, peroxisome proliferator-activated receptor ¦Ã coactivator 1¦Á 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-3¦Â, 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-3¦Â inhibition protected against high glucose-induced mitochondrial and mechanical anomalies, the effect of which was cancelled by mitochondrial uncoupling.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-3¦Â activation and mitochondrial function independent of the global metabolic profile.The mi
%K ALDH2
%K cardiac contraction
%K diabetes
%K GSK3¦Â
%K mitochondrial function
%U http://www.biomedcentral.com/1741-7015/10/40