title: Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function.
abstract: Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated.
  
  
  
  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-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.
  
  
  
  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.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sara A
authors.initials: SA
authors.lastname: Babcock
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Jacalyn R
authors.initials: JR
authors.lastname: Maris
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014463:Ultrasonography; D000071246:Uncoupling Protein 2
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D019831:Sodium-Calcium Exchanger; D015534:Trans-Activators; D014157:Transcription Factors; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium