Circ-CIMIRC inhibition alleviates CIH-induced myocardial damage via FbxL4-mediated ubiquitination of PINK1

Summary: Obstructive sleep apnea (OSA) is a common sleep disordered breathing diseases that characterized by chronic intermittent hypoxia (CIH). This work aimed to explore the role of circ-CIMIRC in CIH-induced myocardial injury. CIH aggravated myocardial tissue damage in rats. Circ_CIMIRC overexpression promoted apoptosis and reduced the colocalization of Tom20 and Parkin and mitophagy in CIH-treated H9c2 cells. Additionally, FbxL4 interacted with PINK1, FbxL4 silencing reduced PINK1 ubiquitination in H9c2 cells. Two major ubiquitination sites (K319 and K433) were responsible for ubiquitination of PINK1. Circ_CIMIRC promoted FbxL4-mediated ubiquitination and degradation of PINK1. Furthermore, circ_CIMIRC inhibition alleviated the pathological damage, fibrosis and apoptosis of myocardial tissues, reduced oxidative stress in CIH rats. In conclusion, circ_CIMIRC silencing repressed FbxL4-mediated ubiquitination and degradation of PINK1 and then enhanced PINK1/Parkin-mediated mitophagy, thereby alleviating myocardial damage in CIH rats. Thus, circ_CIMIRC may be a potential strategy to alleviate CIH-induced myocardial damage.