Abstract
Aims We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.
Highlights
Cardiac hypertrophy is a pathological remodeling process of the heart characterized by hypertrophied cardiomyocytes, interstitial fibrosis, perivascular fibrosis, and decreased cardiac compliance
The results of the present study showed that LCZ696 upregulated sirtuin 3 (Sirt3) expression levels both in hypertrophied cardiac myocytes with transverse aortic constriction and cardiomyocytes induced with phenylephrine (PE)
The mRNA markers of cardiac hypertrophy, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC), referred to as fetal genes, were overtly surged in Transabdominal Cerclage (TAC)-primed hearts compared with the sham group
Summary
Cardiac hypertrophy is a pathological remodeling process of the heart characterized by hypertrophied cardiomyocytes, interstitial fibrosis, perivascular fibrosis, and decreased cardiac compliance. Reactive oxygen species can enhance the progression of cardiac hypertrophy and heart failure [10,11,12,13]. Sirtuin 3 (Sirt3) is the most extensively studied because of the decisive role it plays in a variety of diseases. It has been elaborated that Sirt deficiency exacerbates cardiac hypertrophy and heart failure in transverse aortic constriction mice, whereas Sirt overexpression protects against maladaptive ventricular remodeling [19, 20]. We hypothesized that the potential mechanisms underlying the beneficial effects of LCZ696 on pathological cardiac remodeling could be mediated by the Sirt3-dependent pathway. The results of the present study showed that LCZ696 upregulated Sirt expression levels both in hypertrophied cardiac myocytes with transverse aortic constriction and cardiomyocytes induced with phenylephrine (PE). We observed that the cardioprotective effects of LCZ696 were partly mediated by the Sirt3-dependent pathway
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