Abstract
Histone deacetylase (HDAC) inhibitors have shown cardioprotective or renoprotective effects in various animal models. Our study proposed that the HDAC inhibitor, mocetinostat, regulates cardiac remodelling and renin-angiotensin system (RAS) activity in rats with transverse aortic constriction (TAC)-induced pressure overload cardiac hypertrophy. Cardiac remodelling was evaluated using echocardiography. Cardiac hypertrophy was visualized with haematoxylin and eosin staining, and related gene (Nppa and Nppb) expression was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cardiac and renal fibrosis were visualized with picrosirius red and trichrome staining, respectively. Fibrosis related gene (Collagen-1, Collagen-3, Ctgf, and Fibronectin) expression was determined by qRT-PCR. Serum concentrations of RAS components (renin, angiotensin II, and aldosterone) were quantified by enzyme-linked immunosorbent assay and related gene (Renin and Agtr1) expression was determined by qRT-PCR. TAC-induced pressure overload cardiac hypertrophy, which mimics hypertensive heart disease, increased cardiac remodelling, cardiac hypertrophy, and fibrosis in our rat models. Upon treatment with mocetinostat, there was a significant regression in cardiac remodelling, cardiac hypertrophy, and fibrosis in TAC rats. Additionally, pressure overload-induced renal fibrosis and activity of RAS-related components were increased in TAC rats, and were decreased on treatment with mocetinostat. The present study indicates that mocetinostat, an HDAC inhibitor, has cardiorenal protective effects in rats with TAC-induced pressure overload cardiac hypertrophy and offers a promising therapeutic agent for hypertension-related diseases.
Highlights
Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease
Our study proposed that the Histone deacetylase (HDAC) inhibitor, mocetinostat regulates cardiac remodelling and renin-angiotensin system (RAS) activity in rats with transverse aortic constriction (TAC)-induced pressure overload cardiac hypertrophy
The heart wall thickness of interventricular septum (IVS, p < 0.01) and left ventricular posterior wall (LVPW, p < 0.05) was remarkably increased in TAC group compared with sham group, and mocetinostat treatment considerably regulated the thickness of both IVS (p < 0.05) and LVPW (p < 0.05) in TAC group (Fig. 2a,b)
Summary
Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease. The left ventricle is the primary target of HTN related end-organ damage. In addition to being a marker of HTN, cardiac remodelling of left ventricle occur initially as compensatory responses to increased systemic pressure overload, which modifies the performance and changes the geometry of the heart. Blood pressure control with lifestyle changes and anti-hypertensive agents prevents and regresses left ventricular hypertrophy (LVH) [1, 2]. Progression to end-stage renal disease is relatively low in uncomplicated essential HTN, mild renal dysfunction could occur, such as a subclinical end-organ damage in untreated patients with primary HTN. The presence of LVH could represent a relationship between renal failure and cardiovascular diseases in all stages of renal failure, starting from the earliest stage [3, 4]
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