Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway
Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway
复制标题
亚精胺增强自噬流通过靶向 AMPK/mTOR 信号通路改善心肌梗死后的心脏功能障碍
DOI：
10.1111/bph.14706
复制
发表时间：
2019-07-17
影响因子：
7.3
通讯作者：
Chen, Ai-Hua
中科院分区：
文献类型：
--
作者：
Yan, Jing;Yan, Jian-Yun;Chen, Ai-Hua
背景和目的亚精胺是一种天然多胺，在哺乳动物细胞中含量丰富，参与细胞的生长、增殖和再生。最近，口服亚精胺补充剂通过增强自噬通量对年龄相关性心功能不全具有心脏保护作用。然而，亚精胺对心肌梗死（MI）后心肌损伤和心功能不全的影响尚不清楚。实验方法我们确定了亚精胺在MI模型中的作用，永久结扎左前降支动脉的Sprague-Dawley大鼠，以及暴露于血管紧张素II（Ang II）的培养的新生大鼠心肌细胞（NRC）。用超声心动图评价在体心脏功能。体内和体外研究使用组织学和免疫组织化学技术，沿着蛋白质印迹。亚精胺改善了血管紧张素II处理的NRC的心肌细胞活力，减少了细胞坏死。在大鼠心肌梗死后，亚精胺减少梗死面积，改善心脏功能，并减弱心肌肥厚。亚精胺还能抑制心肌梗死引起的氧化损伤和炎性细胞因子。此外，亚精胺增强自噬流量和减少细胞凋亡在体外和体内。亚精胺对心肌细胞凋亡和心功能不全的保护作用被自噬抑制剂氯喹消除，表明亚精胺至少部分地通过激活AMPK/mTOR信号通路促进自噬通量来发挥心脏保护作用。结论和意义我们的研究结果表明，亚精胺改善MI引起的心功能不全，促进AMPK/mTOR介导的自噬流量。
Background and Purpose Spermidine, a natural polyamine, is abundant in mammalian cells and is involved in cell growth, proliferation, and regeneration. Recently, oral spermidine supplements were cardioprotective in age-related cardiac dysfunction, through enhancing autophagic flux. However, the effect of spermidine on myocardial injury and cardiac dysfunction following myocardial infarction (MI) remains unknown. Experimental Approach We determined the effects of spermidine in a model of MI, Sprague-Dawley rats with permanent ligation of the left anterior descending artery, and in cultured neonatal rat cardiomyocytes (NRCs) exposed to angiotensin II (Ang II). Cardiac function in vivo was assessed with echocardiography. In vivo and in vitro studies used histological and immunohistochemical techniques, along with western blots. Key Results Spermidine improved cardiomyocyte viability and decreased cell necrosis in NRCs treated with angiotensin II. In rats post-MI, spermidine reduced infarct size, improved cardiac function, and attenuated myocardial hypertrophy. Spermidine also suppressed the oxidative damage and inflammatory cytokines induced by MI. Moreover, spermidine enhanced autophagic flux and decreased apoptosis both in vitro and in vivo. The protective effects of spermidine on cardiomyocyte apoptosis and cardiac dysfunction were abolished by the autophagy inhibitor chloroquine, indicating that spermidine exerted cardioprotective effects at least partly through promoting autophagic flux, by activating the AMPK/mTOR signalling pathway. Conclusions and Implications Our findings suggest that spermidine improved MI-induced cardiac dysfunction by promoting AMPK/mTOR-mediated autophagic flux.