Beclin1 haploinsufficiency rescues low ambient temperature-induced cardiac remodeling and contractile dysfunction through inhibition of ferroptosis and mitochondrial injury.

OBJECTIVE:Cold exposure provokes cardiac remodeling and cardiac dysfunction. Autophagy participates in cold stress-induced cardiovascular dysfunction. This study was designed to examine the impact of Beclin1 haploinsufficiency (BECN+/-) in cold stress-induced cardiac geometric and contractile responses. METHODS AND MATERIALS:Wild-type (WT) and BECN+/- mice were assigned to normal or cold exposure (4 °C) environment for 4 weeks prior to evaluation of cardiac geometry, contractile and mitochondrial properties. Autophagy, apoptosis and ferroptosis were evaluated. RESULTS:Our data revealed that cold stress triggered cardiac remodeling, compromised myocardial contractile capacity including ejection fraction, fractional shortening, peak shortening and maximal velocity of shortening/relengthening, duration of shortening and relengthening, intracellular Ca2+ release, intracellular Ca2+ decay, mitochondrial ultrastructural disarray, superoxide production, unchecked autophagy, apoptosis and ferroptosis, the effects of which were negated by Beclin1 haploinsufficiency. Circulating levels of corticosterone were elevated in both WT and BECN+/- mice. Treatment of corticosterone synthesis inhibitor metyrapone or ferroptosis inhibitor liproxstatins-1 rescued cold stress-induced cardiac dysfunction and mitochondrial injury. In vitro study noted that corticosterone challenge compromised cardiomyocyte function, provoked lipid peroxidation and mitochondrial injury, the effects of which were nullified by Beclin1 haploinsufficiency, inhibitors of lipoxygenase, ferroptosis and autophagy. In addition, ferroptosis inducer erastin abrogated Beclin1 deficiency-offered cardioprotection. CONCLUSION:These data suggest that Beclin1 haploinsufficiency protects against cold exposure-induced cardiac dysfunction possibly through corticosterone- and ferroptosis-mediated mechanisms.