Necroptosis mediated by impaired autophagy flux contributes to adverse ventricular remodeling after myocardial infarction

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 dysre- gulation 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 ne- croptotic 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 ne- croptosis by RIP3 knockdown. In conclusion, these results suggested that autophagy dysfunction-mediated ne- croptosis 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.