Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury.
Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury.
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DOI：
10.1161/circresaha.120.318601
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发表时间：
2021-07-23
影响因子：
20.1
通讯作者：
Hill JA
中科院分区：
文献类型：
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作者：
Xie M;Cho GW;Kong Y;Li DL;Altamirano F;Luo X;Morales CR;Jiang N;Schiattarella GG;May HI;Medina J;Shelton JM;Ferdous A;Gillette TG;Hill JA
再灌注损伤占心肌梗死面积的一半，并且不存在针对它的有意义的临床治疗。我们以前曾报道过，自噬在再灌注过程中减少，HDAC抑制增强心肌细胞自噬，并在再灌注时给药时减轻缺血/再灌注（I/R）损伤。然而，诱导自噬本身，而不是HDAC抑制引发的其他影响，是否足以防止再灌注损伤尚不清楚。我们开始测试使用特定的自噬诱导肽Tat-Beclin增强自噬是否通过减少再灌注损伤期间的活性氧（ROS）来保护心肌。将8至12周龄的野生型C57 BL 6小鼠和药物诱导的心肌细胞特异性ATG 7敲除小鼠（以测试对自噬的依赖性）随机分为两组：暴露于对照Tat-杂乱（TS）肽或Tat-Beclin（TB）肽。各组均行冠状动脉结扎45 min，再灌注24 h的I/R手术。测定心肌细胞大小、收缩功能、自噬流量和ROS。培养的新生大鼠心室肌细胞（NRVMs）暴露于TB在模拟缺血/再灌注损伤。在NRVM中通过siRNA敲低ATG 7用于评估自噬的作用。再灌注时TB治疗使梗死面积减少20%（绝对减少;相对减少50%），并改善收缩功能。改善与氧化应激较少的边界区的自噬通量增加相关。ATG 7 KO小鼠在I/R期间没有表现出TB促进的心脏保护作用。在经历I/R的NRVM中，TB使细胞死亡减少41%，并减少I/R诱导的ROS产生。相反，NRVM中的ATG 7敲低消除了TB对细胞死亡和ROS减少的这些有益作用。在再灌注时诱导自噬足以通过减少ROS和细胞死亡来减轻心肌再灌注损伤。维持适当的自噬流量可能成为减少急性心肌梗死再灌注损伤的一种可行的临床疗法。
Reperfusion injury accounts for up to half of myocardial infarct size, and meaningful clinical therapies targeting it do not exist. We have reported previously that autophagy is reduced during reperfusion and that HDAC inhibition enhances cardiomyocyte autophagy and blunts ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, whether inducing autophagy per se, as opposed to other effects triggered by HDAC inhibition, is sufficent to protect against reperfusion injury is not clear. We set out to test whether augmentation of autophagy using a specific autophagy-inducing peptide, Tat-Beclin, protects the myocardium through reduction of reactive oxygen species (ROS) during reperfusion injury. Eight to twelve-week-old, wild-type, C57BL6 mice and drug-inducible cardiomyocyte-specific ATG7 knockout mice (to test the dependency on autophagy) were randomized into two groups: exposed to a control Tat-Scrambled (TS) peptide or a Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min coronary ligation, 24h reperfusion). Infarct size, systolic function, autophagic flux, and ROS were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were exposed to TB during simulated ischemia/reperfusion injury. ATG7 knockdown by siRNA in NRVMs was used to evaluate the role of autophagy. TB treatment at reperfusion reduced infarct size by 20% (absolute reduction; 50% relative reduction) and improved contractile function. Improvement correlated with increased autophagic flux in the border zone with less oxidative stress. ATG7 KO mice did not manifest TB-promoted cardioprotection during I/R. In NRVMs subjected to I/R, TB reduced cell death by 41% and reduced I/R-induced ROS generation. Conversely, ATG7 knockdown in NRVMs abolished these beneficial effects of TB on cell death and ROS reduction. Induction of autophagy at the time of reperfusion is sufficient to mitigate myocardial reperfusion injury by reducing ROS and cell death. Maintenance of appropriate autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in acute myocardial infarction.