Document Detail


Heavy metal scavenger metallothionein mitigates deep hypothermia-induced myocardial contractile anomalies: role of autophagy.
MedLine Citation:
PMID:  23132296     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Low-ambient temperature environment exposure increased the risk of cardiovascular morbidity and mortality, although the underlying mechanism remains unclear. This study was designed to examine the impact of cardiac overexpression of metallothionein, a cysteine-rich heavy metal scavenger, on low temperature (4°C)-induced changes in myocardial function and the underlying mechanism involved, with a focus on autophagy. Cold exposure (4°C for 3 wk) promoted oxidative stress and protein damage, increased left ventricular end-systolic and -diastolic diameter, and suppressed fractional shortening and whole heart contractility, the effects of which were significantly attenuated or ablated by metallothionein. Levels of the autophagy markers LC3B-II, beclin-1, and Atg7 were significantly upregulated with unchanged autophagy adaptor protein p62. Fluorescent immunohistochemistry revealed abundant LC3B puncta in cold temperature-exposed mouse hearts. Coimmunoprecipitation revealed increased dissociation between Bcl2 and Beclin-1. Cold exposure reduced phosphorylation of the autophagy inhibitory signaling molecules Akt and mTOR, increased ULK1 phosphorylation, and dampened eNOS phosphorylation (without changes in their total protein expression). These cold exposure-induced changes in myocardial function, autophagy, and autophagy signaling cascades were significantly alleviated or mitigated by metallothionein. Inhibition of autophagy using 3-methyladenine in vivo reversed cold exposure-induced cardiomyocyte contractile defects. Cold exposure-induced cardiomyocyte dysfunction was attenuated by the antioxidant N-acetylcysteine and the lysosomal inhibitor bafilomycin A1. Collectively, these findings suggest that metallothionein protects against cold exposure-induced cardiac anomalies possibly through attenuation of cardiac autophagy.
Authors:
Shasha Jiang; Rui Guo; Yingmei Zhang; Yunzeng Zou; Jun Ren
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-06
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  304     ISSN:  1522-1555     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-02     Completed Date:  2013-02-27     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E74-86     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Autophagy / drug effects,  genetics,  physiology*
Cardiotonic Agents / metabolism,  pharmacology
Cold Temperature / adverse effects
Free Radical Scavengers / metabolism,  pharmacology
Heart Diseases / etiology*,  genetics,  metabolism,  prevention & control*
Hypothermia / complications*
Male
Metallothionein / genetics,  metabolism,  pharmacology,  physiology*
Metals, Heavy / metabolism
Mice
Mice, Transgenic
Myocardial Contraction / drug effects,  genetics
Myocytes, Cardiac / drug effects,  metabolism,  physiology
Oxidative Stress / drug effects,  genetics
Severity of Illness Index
Grant Support
ID/Acronym/Agency:
8P20-GM-103432/GM/NIGMS NIH HHS; P20-RR-016474/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Free Radical Scavengers; 0/Metals, Heavy; 9038-94-2/Metallothionein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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