Abstract
An important pathophysiological consequence of pressure overload-induced cardiac hypertrophy is adverse cardiac remodeling, including structural changes in cardiomyocytes and extracellular matrix. Diosmetin (DIO), a monomethoxyflavone isolated from citrus fruits, had antioxidative stress effects in multiple organs. The purpose of this study was to examine the biological effect of diosmetin on pathological cardiac hypertrophy. In mice, diosmetin treatment reduced cardiac hypertrophy and dysfunction in an aortic banding- (AB-) induced pressure overload model and reducing myocardial oxidative stress by increasing antioxidant gene expression. In vitro, diosmetin (10 or 50 μm, 12 h or 24 h) protected PE-induced cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. Mechanistically, diosmetin inhibited autophagy by activating the PI3K/Akt pathway. In particular, diosmetin induced the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of Nrf2, and increased the expression of antioxidant stress genes in the process of cardiac hypertrophy. Furthermore, knockdown of p62 in rat primary cardiomyocytes abrogate the protective effect of diosmetin on cardiomyocyte hypertrophy. Similarly, the Nrf2 inhibitor ML385 obviously abolished the above effects by diosmetin treatment. In conclusion, our results suggest that diosmetin protects cardiac hypertrophy under pressure overload through the p62/Keap1/Nrf2 signaling pathway, suggesting the potential of diosmetin as a novel therapy for pathological cardiac hypertrophy.
Highlights
Cardiac hypertrophy is offset by temporary preservation of cardiac output, while persistent pathological cardiac hypertrophy is related to an increased risk of heart failure, arrhythmias, and sudden death [1, 2]
We show that diosmetin treatment have improved cardiac function, as indicated by upregulated contractility (Figure 1(a)), ejection fraction (EF, Figure 1(b)), fractional shortening (FS, Figure 1(c)), interventricular septal thickness at the end-diastole (IVSd, Figure 1(d)), and LV internal diastolic diameter (LVIDd, Figure 1(e)) compared to Aortic banding (AB) controls
We report that diosmetin is correlated with decreased autophagy and decreased reactive oxygen species (ROS) production, upon aortic constriction treatment in mouse
Summary
Cardiac hypertrophy is offset by temporary preservation of cardiac output, while persistent pathological cardiac hypertrophy is related to an increased risk of heart failure, arrhythmias, and sudden death [1, 2]. Treatment choices have considerably improved prognosis and quality of life of patients diagnosed with heart failure, current therapy has at best put off disease progression, rather than providing a curative effect. In addition to traditional mediators of oxidative stress, dysregulation of autophagy and protein homeostasis contribute to pathological cardiac hypertrophy through mechanisms involving oxidative stress [6, 7]. It is widely accepted that autophagy is dysregulated under hemodynamic stress [8]. In this sense, autophagy seems to be an attractive therapeutic target for cardiac diseases. The PI3K/Akt pathway is involved in cardiac hypertrophy by two well-established downstream proteins, mTOR and glycogen synthase kinase-3 (GSK-3), both of which modulate cardiomyocyte autophagy [9,10,11]. The PI3K/Akt pathway is involved in cardiac hypertrophy by two well-established downstream proteins, mTOR and glycogen synthase kinase-3 (GSK-3), both of which modulate cardiomyocyte autophagy [9,10,11]. p62 (sequestosome-1/SQSTM1) serves as a selective autophagy receptor as well as a signaling scaffold to participate in the regulation of multiple physiological processes including oxidative stress defense and cellular metabolism [12,13,14]. p62
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