Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway

• DOI: 10.1016/j.phrs.2024.107057
• Publication Date: 2024-01-11T12:20:48Z
• Authors: Zhangwei Chen; Su Li; Muyin Liu; Ming Yin; Jinxiang Chen; Youran Li; Qiyu Li; You Zhou; Yan Xia; Ao Chen; Danbo Lu; Chenguang Li; Yuqiong Chen; Juying Qian; Junbo Ge
• Keywords: Nicorandil; PINK1; Diabetic Cardiomyopathy

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial and DCM; however, its effects on mitophagy remain unexplored. The present study aimed to assess the beneficial of nicorandil DCM underlying mechanisms. Cardiac perfusion was assessed using a lectin assay, while via mt-Keima transfection transmission electron microscopy. Ferroptosis examined mRNA sequencing, fluorescence staining, western blotting. localization Parkin, ACSL4, AMPK determined immunofluorescence staining. Following long-term diabetes, treatment improved function remodeling by alleviating injuries, as evidenced structural integrity. mRNA-sequencing biochemical analyses showed that occurred Pink1/Parkin-dependent suppressed cells after diabetes. Nicorandil mitochondria-associated promoting mitophagy. Moreover, increased phosphorylation level AMPKα1 promoted translocation, which further inhibited translocation ACSL4 ultimately ferroptosis. Importantly, overexpression mitochondria-localized (mitoAα1) shared similar benefits with mitophagy, cardiovascular protection injury. In conclusion, demonstrated therapeutic revealed AMPK-Parkin-ACSL4 signaling pathway mediates development dysfunction.