Document Detail

Mitochondrial aldehyde dehydrogenase obliterates endoplasmic reticulum stress-induced cardiac contractile dysfunction via correction of autophagy.
MedLine Citation:
PMID:  23354068     Owner:  NLM     Status:  MEDLINE    
ER stress triggers myocardial contractile dysfunction while effective therapeutic regimen is still lacking. Mitochondrial aldehyde dehydrogenase (ALDH2), an essential mitochondrial enzyme governing mitochondrial and cardiac function, displays distinct beneficial effect on the heart. This study was designed to evaluate the effect of ALDH2 on ER stress-induced cardiac anomalies and the underlying mechanism involved with a special focus on autophagy. WT and ALDH2 transgenic mice were subjected to the ER stress inducer thapsigargin (1mg/kg, i.p., 48h). Echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties as well as myocardial histology, autophagy and autophagy regulatory proteins were evaluated. ER stress led to compromised echocardiographic indices (elevated LVESD, reduced fractional shortening and cardiac output), cardiomyocyte contractile and intracellular Ca(2+) properties and cell survival, associated with upregulated autophagy, dampened phosphorylation of Akt and its downstream signal molecules TSC2 and mTOR, the effects of which were alleviated or mitigated by ALDH2. Thapsigargin promoted ER stress proteins Gadd153 and GRP78 without altering cardiomyocyte size and interstitial fibrosis, the effects of which were unaffected by ALDH2. Treatment with thapsigargin in vitro mimicked in vivo ER stress-induced cardiomyocyte contractile anomalies including depressed peak shortening and maximal velocity of shortening/relengthening as well as prolonged relengthening duration, the effect of which was abrogated by the autophagy inhibitor 3-methyladenine and the ALDH2 activator Alda-1. Interestingly, Alda-1-induced beneficial effect against ER stress was obliterated by autophagy inducer rapamycin, Akt inhibitor AktI and mTOR inhibitor RAD001. These data suggest a beneficial role of ALDH2 against ER stress-induced cardiac anomalies possibly through autophagy reduction.
Bingfang Zhang; Yingmei Zhang; Karissa H La Cour; Kacy L Richmond; Xiao-Ming Wang; Jun Ren
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-23
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1832     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-02-20     Completed Date:  2013-06-13     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  574-84     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier B.V. All rights reserved.
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MeSH Terms
Adenine / analogs & derivatives,  pharmacology
Aldehyde Dehydrogenase* / genetics,  metabolism
Arrhythmias, Cardiac / metabolism,  pathology
Calcium / metabolism
Endoplasmic Reticulum* / genetics,  metabolism
Endoplasmic Reticulum Stress / drug effects
Heart Conduction System / abnormalities,  metabolism,  pathology
Mice, Transgenic
Mitochondria / genetics,  metabolism
Myocardial Contraction / genetics*
Myocytes, Cardiac / metabolism,  pathology
TOR Serine-Threonine Kinases / antagonists & inhibitors,  metabolism
Tumor Suppressor Proteins / antagonists & inhibitors,  metabolism
Grant Support
Reg. No./Substance:
0/Tumor Suppressor Proteins; 4JG2LF96VF/tuberous sclerosis complex 2 protein; 5142-23-4/3-methyladenine; EC Dehydrogenase; EC dehydrogenase 2, mouse; EC protein, human; EC Serine-Threonine Kinases; JAC85A2161/Adenine; SY7Q814VUP/Calcium

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