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Mitochondrial aldehyde dehydrogenase obliterates endoplasmic reticulum stress-induced cardiac contractile dysfunction via correction of autophagy.
Biochim Biophys Acta. 2013 Apr; 1832(4):574-84.BB

Abstract

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.

Authors+Show Affiliations

Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23354068

Citation

Zhang, Bingfang, et al. "Mitochondrial Aldehyde Dehydrogenase Obliterates Endoplasmic Reticulum Stress-induced Cardiac Contractile Dysfunction Via Correction of Autophagy." Biochimica Et Biophysica Acta, vol. 1832, no. 4, 2013, pp. 574-84.
Zhang B, Zhang Y, La Cour KH, et al. Mitochondrial aldehyde dehydrogenase obliterates endoplasmic reticulum stress-induced cardiac contractile dysfunction via correction of autophagy. Biochim Biophys Acta. 2013;1832(4):574-84.
Zhang, B., Zhang, Y., La Cour, K. H., Richmond, K. L., Wang, X. M., & Ren, J. (2013). Mitochondrial aldehyde dehydrogenase obliterates endoplasmic reticulum stress-induced cardiac contractile dysfunction via correction of autophagy. Biochimica Et Biophysica Acta, 1832(4), 574-84. https://doi.org/10.1016/j.bbadis.2013.01.013
Zhang B, et al. Mitochondrial Aldehyde Dehydrogenase Obliterates Endoplasmic Reticulum Stress-induced Cardiac Contractile Dysfunction Via Correction of Autophagy. Biochim Biophys Acta. 2013;1832(4):574-84. PubMed PMID: 23354068.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial aldehyde dehydrogenase obliterates endoplasmic reticulum stress-induced cardiac contractile dysfunction via correction of autophagy. AU - Zhang,Bingfang, AU - Zhang,Yingmei, AU - La Cour,Karissa H, AU - Richmond,Kacy L, AU - Wang,Xiao-Ming, AU - Ren,Jun, Y1 - 2013/01/23/ PY - 2012/11/17/received PY - 2013/01/02/revised PY - 2013/01/15/accepted PY - 2013/1/29/entrez PY - 2013/1/29/pubmed PY - 2013/6/14/medline SP - 574 EP - 84 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1832 IS - 4 N2 - 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. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/23354068/Mitochondrial_aldehyde_dehydrogenase_obliterates_endoplasmic_reticulum_stress_induced_cardiac_contractile_dysfunction_via_correction_of_autophagy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(13)00027-6 DB - PRIME DP - Unbound Medicine ER -