Cold exposure-induced cardiomyocyte dysfunction was attenuated by the antioxidant N-acetylcysteine and the lysosomal inhibitor bafilomycin A1. Inhibition of autophagy using 3-methyladenine in vivo reversed cold exposure-induced cardiomyocyte contractile defects. These cold exposure-induced changes in myocardial function, autophagy, and autophagy signaling cascades were significantly alleviated or mitigated by metallothionein. 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). Coimmunoprecipitation revealed increased dissociation between Bcl2 and Beclin-1. Fluorescent immunohistochemistry revealed abundant LC3B puncta in cold temperature-exposed mouse hearts. Levels of the autophagy markers LC3B-II, beclin-1, and Atg7 were significantly upregulated with unchanged autophagy adaptor protein p62. Cold exposure (4☌ 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. This study was designed to examine the impact of cardiac overexpression of metallothionein, a cysteine-rich heavy metal scavenger, on low temperature (4☌)-induced changes in myocardial function and the underlying mechanism involved, with a focus on autophagy.
Low-ambient temperature environment exposure increased the risk of cardiovascular morbidity and mortality, although the underlying mechanism remains unclear.
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