title: Alcohol Dehydrogenase Protects against Endoplasmic Reticulum Stress-Induced Myocardial Contractile Dysfunction via Attenuation of Oxidative Stress and Autophagy: Role of PTEN-Akt-mTOR Signaling.
abstract: The endoplasmic reticulum (ER) plays an essential role in ensuring proper folding of the newly synthesized proteins. Aberrant ER homeostasis triggers ER stress and development of cardiovascular diseases. ADH is involved in catalyzing ethanol to acetaldehyde although its role in cardiovascular diseases other than ethanol metabolism still remains elusive. This study was designed to examine the impact of ADH on ER stress-induced cardiac anomalies and underlying mechanisms involved using cardiac-specific overexpression of alcohol dehydrogenase (ADH).
  
  
  
  ADH and wild-type FVB mice were subjected to the ER stress inducer tunicamycin (1 mg/kg, i.p., for 48 hrs). Myocardial mechanical and intracellular Ca(2+) properties, ER stress, autophagy and associated cell signaling molecules were evaluated.
  
  
  
  ER stress compromised cardiac contractile function (evidenced as reduced fractional shortening, peak shortening, maximal velocity of shortening/relengthening, prolonged relengthening duration and impaired intracellular Ca(2+) homeostasis), oxidative stress and upregulated autophagy (increased LC3B, Atg5, Atg7 and p62), along with dephosphorylation of PTEN, Akt and mTOR, all of which were attenuated by ADH. In vitro study revealed that ER stress-induced cardiomyocyte anomaly was abrogated by ADH overexpression or autophagy inhibition using 3-MA. Interestingly, the beneficial effect of ADH was obliterated by autophagy induction, inhibition of Akt and mTOR. ER stress also promoted phosphorylation of the stress signaling ERK and JNK, the effect of which was unaffected by ADH transgene.
  
  
  
  Taken together, these findings suggested that ADH protects against ER stress-induced cardiac anomalies possibly via attenuation of oxidative stress and PTEN/Akt/mTOR pathway-regulated autophagy.
authors.affiliation: Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.|Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, United States of America.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Pang
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, United States of America.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Fuller
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, United States of America.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, United States of America.
authors.forename: Linzi A
authors.initials: LA
authors.lastname: Barton
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, United States of America.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Henion
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, United States of America.|Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D019076:Transgenes; D014415:Tunicamycin / Q000633:toxicity; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology
chemical_list: D011993:Recombinant Fusion Proteins; D014415:Tunicamycin; C025946:3-methyladenine; D000426:Alcohol Dehydrogenase; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000225:Adenine; D002118:Calcium; D020123:Sirolimus