Department of Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
Affiliated Guangxi International Zhuang Medical Hospital, Guangxi University of Traditional Chinese Medicine, Nanning 530021, PR China.
Biochem Pharmacol. 2020 May;175:113915. doi: 10.1016/j.bcp.2020.113915. Epub 2020 Mar 14.
Loss of functional cardiomyocytes by cell death after myocardial infarction is most critical for the subsequent left ventricular remodeling, cardiac dysfunction and heart failure. Numerous studies have implicated that dysregulation of autophagy might contribute to cardiomyocyte death. However, the underlying mechanisms by which autophagy dysregulation-mediated cell death remains to be elusive. Herein, we showed that,in response to myocardial ischemic damage in vivo and in vitro, autophagy activity was increased quickly but followed by the process of impaired autophagic degradation as evidenced by the sustained higher level of beclin1 until 12 weeks after myocardial infarction, while, increased accumulation of LC3 and p62. The results from both tandem mRFP-GFP-LC3 adenovirus and lysosomal inhibitor chloroquine supported defective autophagy induction by ischemia injury. Importantly, we found that the impaired autophagy flux, induced not only pharmacologically by CQ but also genetically by beclin1 knockdown, upregulated the expression of RIP3 and aggravated OGD-induced necroptotic cardiomyocyte death and cardiac dysfunction. While, upregulation of autophagy by cardiac-specific beclin1 overexpression partially ameliorated cardiac dysfunction after MI. Furthermore, constitutive activation of necroptosis by forced cardiac-specific overexpression of RIP3 aggravated necrotic cardiomyocyte death, post-MI cardiac remodeling and cardiac dysfunction, but all of which could be ameliorated by inhibition of necroptosis by RIP3 knockdown. In conclusion, these results suggested that autophagy dysfunction-mediated necroptosis mechanistically contributed to loss of cardiomyocytes, adverse ventricular remodeling and progressive heart failure after myocardial Infarction. Inhibition of necroptosis might be the potential target for preventing post-infarction cardiac remodeling and heart failure.
心肌梗死后，通过细胞死亡导致功能性心肌细胞丧失，这对随后的左心室重构、心功能障碍和心力衰竭最为关键。大量研究表明，自噬失调可能导致心肌细胞死亡。然而，自噬失调介导的细胞死亡的潜在机制仍不清楚。在此，我们发现，在体内和体外心肌缺血损伤的情况下，自噬活性迅速增加，但随后自噬降解过程受损，证据是 beclin1 水平持续升高，直到心肌梗死后 12 周，而 LC3 和 p62 的积累增加。串联 mRFP-GFP-LC3 腺病毒和溶酶体抑制剂氯喹的结果均支持缺血损伤诱导的自噬缺陷。重要的是，我们发现，受损的自噬流，不仅可以通过 CQ 药理学诱导，也可以通过 beclin1 敲低遗传学诱导，上调 RIP3 的表达，并加重 OGD 诱导的坏死性心肌细胞死亡和心功能障碍。而心脏特异性 beclin1 过表达上调自噬部分改善了 MI 后的心功能障碍。此外，通过心脏特异性过表达 RIP3 强制激活坏死性细胞死亡会加重心肌梗死后的心肌坏死、心室重构和心功能障碍，但通过 RIP3 敲低抑制坏死性细胞死亡均可改善这些情况。总之，这些结果表明，自噬功能障碍介导的坏死性细胞死亡是心肌梗死后心肌细胞丢失、心室重构不良和心力衰竭进展的机制。抑制坏死性细胞死亡可能是预防梗死后心脏重构和心力衰竭的潜在靶点。
