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 chain20 (MLC20) 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 MLC20 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.
Highlights
The obese and overweight population is increasing rapidly worldwide due to excessive energy intake from a western diet and lack of physical activity (Popkin and Gordon-Larsen 2004)
Our previous study showed that increased basal myosin light chain 20 (MLC20) phosphorylation and consequent vascular smooth muscle hyper-contractility by enhanced Angiotensin II (Ang II) in high-fat diets (HFD) induced hypertension in rat (Kim 2017)
To induce obesity-mediated hypertension, mice were randomly divided into two groups and fed a normal diet (ND) or HFD for 17 weeks
Summary
The obese and overweight population is increasing rapidly worldwide due to excessive energy intake from a western diet and lack of physical activity (Popkin and Gordon-Larsen 2004). Obesity is known to induce hypertension through activating renin-angiotensin-aldosterone system in the kidney (Thethi et al 2012). Angiotensin II (Ang II) induces vasoconstriction and consequent blood pressure elevation (Satou et al 2018). Our previous study showed that increased basal myosin light chain 20 (MLC20) phosphorylation and consequent vascular smooth muscle hyper-contractility by enhanced Ang II in high-fat diets (HFD) induced hypertension in rat (Kim 2017). Ca2+-independent chronic activation of RhoA-activated coiled coil kinase (ROCK) phosphorylates myosin phosphatase target subunit (MYPT1) of myosin light chain phosphatase (MLCP) resulting in reduced activity of MLCP and consequent MLC20 phosphorylation and vascular contraction (Wirth 2010)
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