Histone deacetylase inhibitor CG200745 ameliorates high-fat diet-induced hypertension via inhibition of angiotensin II production

Abstract

Obesity is growing rapidly worldwide due to consumption of westernized diet and lack of exercise. Obesity is one of the major risk factors of hypertension. The novel histone deacetylase (HDAC) inhibitor CG200745 was originally developed to treat various cancers. Previous studies showed that CG200745 attenuated hypertension through inhibition of cardiac hypertrophy and fibrosis in deoxycorticosterone acetate-induced hypertensive rat. The purpose of this study is to investigate the role and underlying mechanism of CG200745 in high-fat diet (HFD)-induced hypertension. Nine-week old C57BL/6 mice were fed a normal diet (ND) or HFD for 17 weeks. Each group of mice was treated with vehicle or CG200745 by intraperitoneal injection for 9 days. HFD group showed higher body weight, blood pressure (BP), HDAC activities, angiotensinogen and renin expressions in kidney, angiotensin-converting enzyme (ACE) expression in the lung, serum angiotensin II (Ang II) concentration, and myosin light chain 20 (MLC 20) phosphorylation in mesenteric artery compared with ND group. CG200745 lowered BP, HDAC activity, renin and angiotensinogen in the kidney, ACE in the lung, serum Ang II level, and phosphorylation of MLC 20 in HFD group. In conclusion, CG200745 ameliorated HFD-induced hypertension through inhibition of HDAC/Ang II/vascular contraction axis. Our results offer CG200745 as a novel therapeutic option for HFD-induced hypertension.

Acute Kidney Injury Results in Long-Term Diastolic Dysfunction That Is Prevented by Histone Deacetylase Inhibition

“…Yoon et al. showed Class I HDACi-treated hypertension in an obesity murine model via inhibition of angiotensin II ( 46 ). However, in our model, there was no significant difference in plasma renin levels at the 12-month time point, indicating that the renin-angiotensin-aldosterone system was not driving the hypertension in the AKI cohort.…”

The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders

“…This finding has prompted interest in SIRT1 as a potential pharmacological target for obesity and obesity-related diseases [ 173 , 175 ]. Recent studies in mouse models of obesity have already demonstrated that HDAC inhibitors stimulate adipose tissue function and oxidative potential, improving the metabolic profile [ 176 , 177 , 178 ]. Additionally, epigenetic changes upon PPARγ-ligand binding have been studied in relation to their effects on adipogenesis.…”

Histone deacetylase inhibitor, mocetinostat, regulates cardiac remodelling and renin-angiotensin system activity in rats with transverse aortic constriction-induced pressure overload cardiac hypertrophy

“…Various studies have shown that histone deacetylase (HDAC) inhibitors are effective in the treatment of cancer, autoimmune diseases, inflammatory diseases, interstitial fibrosis, cardiovascular diseases, and renal diseases [7,8]. Our previous studies reported that valproic acid has cardiac and vascular protective effects [2] and mocetinostat attenuates aortic remodelling [9] in pressure overload-induced cardiac hypertrophy.…”

“…Trichostatin A, valproic acid, and SK-7041 prevent hypertrophy of the heart in animal models of angiotensin II-infused cardiac hypertrophy [13]. Valproic acid ameliorates the angiotensinogen II production in the kidney in high-fat diet-induced HTN model [7]. Trichostatin A [14] and CG200745 [15] attenuate renal fibrosis in unilateral ureteral obstruction mouse model.…”