Department of Cardiovascular Surgery, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science, Shenzhen 518020, China.
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Metabolism. 2020 Dec;113:154397. doi: 10.1016/j.metabol.2020.154397. Epub 2020 Oct 12.
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.
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.
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 Ca release, intracellular Ca 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.
These data suggest that Beclin1 haploinsufficiency protects against cold exposure-induced cardiac dysfunction possibly through corticosterone- and ferroptosis-mediated mechanisms.
寒冷暴露会引起心脏重构和心功能障碍。自噬参与冷应激诱导的心血管功能障碍。本研究旨在探讨 Beclin1 杂合不足（BECN）对冷应激诱导的心脏几何形状和收缩反应的影响。
野生型（WT）和 BECN 小鼠被分配到正常或冷暴露（4°C）环境中 4 周，然后评估心脏几何形状、收缩和线粒体特性。评估自噬、细胞凋亡和铁死亡。
我们的数据表明，冷应激引发心脏重构，损害心肌收缩能力，包括射血分数、缩短分数、峰值缩短和缩短/延长最大速度、缩短和延长持续时间、细胞内 Ca 释放、细胞内 Ca 衰减、线粒体超微结构紊乱、超氧化物产生、不受控制的自噬、细胞凋亡和铁死亡，Beclin1 杂合不足可消除这些作用。WT 和 BECN 小鼠的循环皮质酮水平升高。皮质酮合成抑制剂甲吡酮或铁死亡抑制剂 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，皮质酮刺激会损害心肌细胞功能，引发脂质过氧化和线粒体损伤，Beclin1 杂合不足、脂氧合酶抑制剂、铁死亡和自噬抑制剂可消除这些作用。此外，铁死亡诱导剂 erastin 消除了 Beclin1 缺乏提供的心脏保护作用。
这些数据表明，Beclin1 杂合不足可通过皮质酮和铁死亡介导的机制预防冷暴露引起的心脏功能障碍。
