Format

Send to

Choose Destination
See comment in PubMed Commons below
Am J Physiol Endocrinol Metab. 2013 Jan 1;304(1):E74-86. doi: 10.1152/ajpendo.00176.2012. Epub 2012 Nov 6.

Heavy metal scavenger metallothionein mitigates deep hypothermia-induced myocardial contractile anomalies: role of autophagy.

Author information

1
Institute of Biomedical Sciences, Fudan University, Shanghai, China.

Abstract

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.

PMID:
23132296
PMCID:
PMC3543534
DOI:
10.1152/ajpendo.00176.2012
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center