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.

中文翻译：

---

Beclin1单倍体不足可通过抑制肥大症和线粒体损伤来挽救低环境温度引起的心脏重塑和收缩功能障碍

目的

冷暴露会引起心脏重塑和心脏功能障碍。自噬参与冷应激诱导的心血管功能障碍。这项研究旨在检查Beclin1单倍剂量不足（BECN ^+/-）在冷应激诱导的心脏几何和收缩反应中的作用。

方法和材料

在评估心脏的几何形状，收缩和线粒体特性之前，将野生型（WT）和BECN ^+/-小鼠置于正常或冷暴露（4°C）环境中4周。评估自噬，细胞凋亡和肥大症。

结果

我们的数据显示，冷应激会触发心脏重构，损害心肌收缩能力，包括射血分数，分数缩短，峰缩短和最大缩短/延长速度，缩短和延长时间，细胞内Ca ²⁺释放，细胞内Ca ²⁺衰减，线粒体超微结构紊乱，超氧化物生成，自噬自控，凋亡和肥大病，其影响被Beclin1单倍体功能不足所抵消。WT和BECN ^+/-中皮质激素的循环水平均升高老鼠。皮质类固醇合成抑制剂美拉酮或肥大病抑制剂liproxstatins-1的治疗挽救了冷应激引起的心脏功能障碍和线粒体损伤。体外研究表明，皮质酮攻击会损害心肌细胞功能，引起脂质过氧化和线粒体损伤，其作用被Beclin1单倍剂量不足，脂氧合酶抑制剂，肥大症和自噬作用抵消。此外，促红细胞生成素诱导蛋白废除Beclin1缺乏提供的心脏保护作用。

结论

这些数据表明，Beclin1单倍体功能不足可能通过皮质类固醇和肥大病的介导机制预防了冷暴露引起的心脏功能障碍。