The role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of myocardial ischemia-reperfusion.

Abstract

Myocardial damage caused by myocardial ischemia-reperfusion injury (MIRI) is difficult to be alleviated because cardiomyocyte necrosis is an irreversible and unregulated death form. Recently, necroptosis, a necrosis form caused by tumor necrosis factor-α (TNF-α) and Fas ligand (FasL), was found to be regulated by receptor interacting protein 3 (RIP3) and RIP3-receptor interacting protein 1 (RIP1)-mixed lineage kinase domain like protein (MLKL) pathway. But it is unclear whether they also play a regulatory role in MIRI-induced necroptosis. Our previous results showed that in rat MIRI, RIP3 could translocate and express highly in mitochondria. Therefore, it is important to explore proteins that interact with RIP3 which was translocated to mitochondria. The aim of this study was to explore the role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of hypoxia/reoxygenation (H/R). Our results showed that H/R could cause RIP3-depended mitochondrial fragmentation and necrosis-based death; and RIP3-promoted H/R-induced necroptosis in H9c2 cells through increasing lactate dehydrogenase release and inhibiting cell viability. This process did not require RIP1 or MLKL but dynamin-related protein 1 (Drp1), which was related to Drp1 activation, reactive oxygen species elevation, and ΔΨm decline. This study provides novel insights into the role of RIP3 in cardiomyocyte injury during H/R. RIP3 may serve as a potential target for the treatment of MIRI.