Alleviation of fibrosis and oxidative stress in pressure overload-induced cardiac remodeling and heart failure via SIRT3 activation by colchicine

Abstract

Heart failure (HF) is the end stage of many cardiovascular diseases, which is often associated with myocardial hypertrophy and cardiac remodeling. Among them, pressure overload-induced myocardial injury is one of the most common causes of heart failure. Colchicine, a drug widely used in the treatment of inflammatory diseases, has recently been found to significantly reduce the risk of cardiovascular events in patients with coronary artery disease and atrial fibrillation. However, the specific mechanism of colchicine has not been fully elucidated. We used the transverse aortic constriction (TAC) model to simulate cardiac pressure overload in mice. We found that colchicine attenuated TAC-induced heart failure and alleviated cardiac oxidative stress and fibrosis. To explore the specific molecular mechanism, we treated primary cardiac fibroblasts (CFs) and HL-1 with Ang Ⅱ in vitro to simulate the occurrence of TAC model. We found that colchicine induced SIRT3 activation and alleviated myocardial oxidative stress and cadiac fibrosis. Additionally, the SIRT3-selective agonist HKL exerts similar effects to colchicine, whereas the SIRT3-selective inhibitor 3-TYP partially reverses the therapeutic effects of colchicine. Our findings suggest that colchicine reduced cardiac oxidative stress and fibrosis by activating SIRT3, which in turn alleviated the progression of pressure overload-induced heart failure.