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Nature子刊:中科院健康所杨黄恬研究组发现天然化合物小檗胺后处理能抵抗心肌缺血/复灌损伤

摘要 : 2017年2月2日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了上海生科院健康院杨黄恬研究组题为“Berbamine postconditioning protects the heart from ischemia/reperfusion injury through modulation of autophagy” 的最新研究成果

2017年2月2日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了上海生科院健康院杨黄恬研究组题为“Berbamine postconditioning protects the heart from ischemia/reperfusion injury through modulation of autophagy” 的最新研究成果,研究揭示了天然小檗科植物提取的化合物小檗胺后处理(berbamine postconditioning, BMPoC)在心肌缺血复灌(ischemia/reperfusion, I/R)过程保护心肌损伤的作用机制。博士研究生郑妍俊为论文第一作者,杨黄恬研究员为论文通讯作者。

心肌梗塞后及时恢复缺血区的血供(再灌注)是挽救缺血心肌的必需步骤,但该过程伴随着严重再灌注损伤的发生。再灌注初期自噬(autophagy)调节凋亡紊乱近几年被认为是造成这一损伤的主要因素之一。研究人员发现在缺血前给予berbamine,可剂量依赖性改善缺血后心肌收缩功能和减少心肌细胞死亡。然而作为更有临床应用前景的后处理,berbamine的心肌保护作用及其潜在的分子机制更为值得探究。

研究发现BMPoC剂量依赖性地改善离体心脏缺血复灌后的心功能、改善心肌细胞收缩、减少心肌细胞死亡和降低心肌梗死面积。此作用与BMPoC下调再灌注初期心肌细胞自噬水平并且促进自噬体清除密切相关。通过在体过表达及下调自噬关键基因beclin1发现BMPoC对自噬的调节作用是通过降低复灌初期Beclin1表达水平来实现。进一步研究发现,心肌保护性信号通路PI3K/Akt 参与了BMPoC的保护作用。研究结果揭示了小檗胺后处理的心肌保护新作用,并揭示这一保护作用是通过激活PI3K/Akt信号通路从而抑制Beclin1的表达,进而改善复灌期间的自噬功能紊乱(降低自噬水平以及促进自噬流),为小檗胺走向临床应用提供了新的理论基础。

原文链接:

Berbamine postconditioning protects the heart from ischemia/reperfusion injury through modulation of autophagy

原文摘要:

Pretreatment of berbamine protects the heart from ischemia/reperfusion (I/R) injury. However it is unknown whether it has cardioprotection when given at the onset of reperfusion (postconditioning (PoC)), a protocol with more clinical impact. Autophagy is upregulated in I/R myocardium and exacerbates cardiomyocyte death during reperfusion. However, it is unknown whether the autophagy during reperfusion is regulated by berbamine. Here we investigated whether berbamine PoC (BMPoC) protects the heart through regulation of autophagy by analyzing the effects of BMPoC on infarct size and/or cell death, functional recovery and autophagy in perfused rat hearts and isolated cardiomyocytes subjected to I/R. Berbamine from 10 to 100 nM given during the first 5 min of reperfusion concentration-dependently improved post-ischemic myocardial function and attenuated cell death. Similar protections were observed in cardiomyocytes subjected to simulated I/R. Meanwhile, BMPoC prevented I/R-induced impairment of autophagosome processing in cardiomyocytes, characterized by increased LC3-II level and GFP-LC3 puncta, and decreased p62 degradation. Besides, lysosomal inhibitor chloroquine did not induce additional increase of LC3-II and P62 abundance after I/R but it reversed the effects of BMPoC in those parameters in cardiomyocytes, suggesting that I/R-impaired autophagic flux is restored by BMPoC. Moreover, I/R injury was accompanied by enhanced expression of Beclin 1, which was significantly inhibited by BMPoC. In vitro and in vivo adenovirus-mediated knockdown of Beclin 1 in myocardium and cardiomyocytes restored I/R-impaired autophagosome processing, associated with an improvement of post-ischemic recovery of myocardial contractile function and a reduction of cell death, but it did not have additive effects to BMPoC. Conversely, overexpression of Beclin 1 abolished the cardioprotection of BMPoC as did by overexpression of an essential autophagy gene Atg5. Furthermore, BMPoC-mediated cardioprotection was abolished by a specific Akt1/2 inhibitor A6730. Our results demonstrate that BMPoC confers cardioprotection by modulating autophagy during reperfusion through the activation of PI3K/Akt signaling pathway.

来源: Cell Death & Differentiation 浏览次数:0

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