Beclin-1-Dependent Autophagy Protects the Heart During Sepsis.
Beclin-1-Dependent Autophagy Protects the Heart During Sepsis.
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DOI：
10.1161/circulationaha.117.032821
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发表时间：
2018-11-13
期刊：
影响因子：
37.8
通讯作者：
Zang QS
中科院分区：
文献类型：
--
作者：
Sun Y;Yao X;Zhang QJ;Zhu M;Liu ZP;Ci B;Xie Y;Carlson D;Rothermel BA;Sun Y;Levine B;Hill JA;Wolf SE;Minei JP;Zang QS
在重症监护病房中，心功能障碍是脓毒症诱导的多器官衰竭的一个主要组成部分。心脏自噬的变化及其在脓毒症发病机制中的作用尚未明确界定。基于自噬的脓毒症靶向治疗方法尚未开发出来。
在脂多糖（LPS）诱导的脓毒症小鼠模型中，研究了脓毒症期间心脏中依赖于Beclin - 1的自噬以及靶向该通路的潜在治疗益处。
LPS在低剂量时诱导自噬呈剂量依赖性增加，随后在高剂量时随着mTOR激活而下降。心脏特异性过表达Beclin - 1促进自噬，抑制mTOR信号传导，改善心脏功能，并减轻LPS刺激后的炎症和纤维化。Beclin 1单倍体不足导致相反的效果。Beclin - 1还保护线粒体，减少线粒体损伤相关分子模式（DAMPs）的释放，并通过PINK1 - Parkin（而非衔接蛋白）促进线粒体自噬以应对LPS。注射一种可透细胞的Tat - Beclin - 1肽来激活自噬可改善心脏功能，减轻炎症，并挽救LPS刺激的小鼠中由Beclin 1缺乏引起的表型。
这些结果表明，Beclin - 1在脓毒症期间保护心脏，并且靶向诱导Beclin - 1信号传导可能具有重要的治疗潜力。
Cardiac dysfunction is a major component of sepsis-induced multi-organ failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed. Beclin-1-dependent autophagy in the heart during sepsis and the potential therapeutic benefit of targeting this pathway were investigated in a mouse model of lipopolysaccharide (LPS)-induced sepsis. LPS induced a dose-dependent increase in autophagy at low doses, followed by a decline that was in conjunction with mTOR activation at high doses. Cardiac-specific overexpression of Beclin-1 promoted autophagy, suppressed mTOR signaling, improved cardiac function, and alleviated inflammation and fibrosis after LPS challenge. Haplosufficiency for beclin 1 resulted in opposite effects. Beclin-1 also protected mitochondria, reduced the release of mitochondrial DAMPs, and promoted mitophagy via PINK1-Parkin but not adaptor proteins in response to LPS. Injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by beclin 1 deficiency in LPS-challenged mice. These results suggest that Beclin-1 protects the heart during sepsis and that the targeted induction of Beclin-1 signaling may have important therapeutic potential.