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  • Title: Atorvastatin Improves Doxorubicin-Induced Cardiac Dysfunction by Modulating Hsp70, Akt, and MAPK Signaling Pathways.
    Author: Gao G, Jiang S, Ge L, Zhang S, Zhai C, Chen W, Sui S.
    Journal: J Cardiovasc Pharmacol; 2019 Apr; 73(4):223-231. PubMed ID: 30540688.
    Abstract:
    Atorvastatin is a lipid-regulating drug that is commonly used in clinical practice and can stabilize plaques. Increasing evidence shows that statins have anti-heart failure (HF) effects, but their specific mechanism is not clear. The purpose of this study was to investigate the cardioprotective effects of atorvastatin on HF in rats and its mechanism. Continuous intraperitoneal injection of 2.5 mg/kg/w doxorubicin for 6 weeks, with a cumulative dose of 15 mg/kg, was used to induce a rat model of HF. Then, the rats were treated with low-dose atorvastatin, high-dose atorvastatin, or saline for 4 weeks. In the DOX-treated groups, echocardiography showed decreases in left ventricular ejection fraction and fractional shortening and increases in left ventricular end-diastolic diameter and left ventricular posterior wall thickness compared with those in the control group, and increased levels of brain natriuretic peptide and Hsp70 were also found in the doxorubicin-treated groups. Compared with saline intervention, atorvastatin ameliorated left ventricular ejection fraction, fractional shortening, left ventricular end-diastolic diameter, and left ventricular posterior wall thickness (a significant difference was observed only in the high-dose group) and reduced serum brain natriuretic peptide. Hematoxylin and eosin staining showed that atorvastatin ameliorated myocardial injury. The improvement in cardiac function induced by atorvastatin was accompanied by increased Hsp70 expression, decreased p-ERK and p-JNK expression, and a reduction in myocardial fibrosis shown by Masson staining. In addition, atorvastatin had a protective effect on the myocardial apoptosis signaling pathway, with increased p-Akt expression and downregulated cleaved caspase-3 expression, and the reduction in myocardial apoptosis was confirmed by a TUNEL assay. Therefore, our experiments demonstrated that atorvastatin may protect cardiac function by modulating Hsp70, p-Akt, p-ERK, and p-JNK signaling to reduce myocardial fibrosis and myocardial apoptosis.
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