AP39 ameliorates uremic myocardial fibrosis in rats by upregulating PINK1/Parkin-mediated mitochondrial autophagy

Abstract

Objective To elucidate the ameliorative effect of AP39 on myocardial fibrosis in uremic rats and investigate its possible mechanism. Methods Forty SD male rats were randomly and equally divided into 4 groups: Sham group, uremic cardiomyopathy group (UCM group), AP39 intervention group (UCM+AP39 group) and AP39 control group (n=10). The rats in the UCM group and the UCM+AP39 group were treated with classical operation of 5/6 nephrectomy to establish the uremic cardiomyopathy model, and then the rats in the latter 2 groups were given intraperitoneal injection of AP39 (100 nmol/kg, once a day) for 4 weeks, while those of the Sham and model groups were intraperitoneally injected with the same amount of normal saline. Ultrasonic imaging platform was used to detect the value of left ventricular fractional shortening (LVFS) of rats in each group. Masson staining and immunohistochemical staining were performed respectively to observe collagen deposition and the expression of Collagen Ⅲ protein in the myocardial interstitial tissue of each group. Western blotting was adopted to determine the expression levels of PETN-induced putative kinase-1 (PINK1), Parkinson's disease protein (Parkin), autophagy-related gene-5 (Atg5), microtubule-associated protein-1 light chain-3 Ⅱ/Ⅰ(LCEⅡ/Ⅰ), Beclin1 and P62 (also called sequestosome, SQSTM1) in the myocardial tissue of each group. Results As compared with those in the Sham group, the rats in the UCM group had significantly decreased LVFS, increased collagen deposition content and Collagen Ⅲ protein level (P < 0.05), and disordered arrangement in myocardial tissue. The expression levels of PINK1, Parkin, Atg5, LC3Ⅱ/Ⅰand Beclin1 were significantly reduced, while the level of P62 was enhanced in the UCM group (P < 0.05). By contrast, the rats in the UCM+AP39 group had higher LVFS, lower collagen deposition content and Collagen Ⅲ protein level than those in the UCM group (P < 0.05), the expression levels of PINK1, Parkin, Atg5, LC3 Ⅱ/Ⅰ and Beclin1 were remarkably up-regulated, and the level of P62 down-regulated (P < 0.05). Conclusion AP39 can improve uremic myocardial fibrosis in rats, which may be related to the up-regulation of PINK1/Parkin-mediated mitophagy.

Keywords

• ap39
• myocardial fibrosis
• uremic cardiomyopathy
• mitophagy
• pink1/parkin pathway