Vanillic acid attenuates doxorubicin-induced cardiotoxicity by regulating PINK1/Parkin/Mfn2 signaling pathway

The aim of this study was to explore the potential protective effects of vanillic acid (VA) against doxorubicin (DOX)-induced cardiotoxicity and unravel the underlying molecular mechanisms involved. The DOX -induced myocardial toxicity model was established in Sprague-Dawley (SD) rats by intraperitoneal injection of doxorubicin. Simultaneously, different concentrations of VA were administered for intervention. After modeling, rat cardiac function was evaluated using an ultrasound machine. The detection of creatine kinase isoenzyme MB (CK-MB) levels in rat serum using a biochemical analyzer. HE staining method was used to observe myocardial pathological changes, Masson's trichrome staining was performed to assess the degree of myocardial fibrosis. The observation of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels in myocardial tissue using assay kits. Western blotting and immunohistochemistry was conducted to detect protein expression levels of PINK1, Parkin, P62, LC3I/II, Mfn2, Drp1, OPA, and Fis1. Compared to the DOX group, intervention with VA demonstrates ameliorative effects on doxorubicin-induced cardiotoxicity, as evidenced by improvements in left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and a reduction in left ventricular end-diastolic diameter (LVEDd) in rats. Additionally, the application of VA reduced the levels of CK-MB in rat serum. However, there were no statistically significant differences observed in heart rate. Histological examination reveals that VA administration positively impacts the arrangement of myocardial fibers and mitigates myocardial fibrosis in the rat hearts subjected to doxorubicin-induced injury. Moreover, relative to the DOX group, the use of VA alleviates DOX-induced myocardial cell apoptosis. VA treatment also upregulates the expression levels of PINK1 and Parkin, leading to the activation of mitochondrial autophagy. Furthermore, VA enhances the expression levels of mitochondrial dynamics proteins Mfn2, Drp1, and Fis1 while downregulating the expression of OPA. Among them, the high-dose group of VA (60 mg/kg·d) showed the most pronounced improvement in DOX-induced cardiotoxicity. VA attenuated DOX-induced myocardial injury by up regulating the PINK1/Parkin/Mfn2 signaling pathway. • Our study is the first to discover that VA can protect against the cardiotoxicity of DOX. • It has been demonstrated that VA may exert its effects by regulating the PINK1/Parkin/Mfn2 signaling pathway. • VA can activate the level of autophagy in cardiac tissue caused by DOX-induced cardiotoxicity.