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 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.

Keywords: Ang II; HDAC activity; HDAC inhibitor; Hypertension; Obesity.

Fig. 1

Increased body weight and blood pressure by HFD. Mice were fed either ND or HFD for 17 weeks. Blood pressure was measured using the tail-cuff method. Graphs summarize body weight (a), systolic blood pressure (b), and diastolic blood pressure (c). HFD accelerated increase in body weight and blood pressure. Results are expressed as the mean ± SE (n = 5–8 mice per group). ND, normal diet; HFD, high-fat diet

Fig. 2

Blood pressure and body weight after treatment of CG200745 in ND- and HFD-fed mice. Graphs summarize systolic blood pressure (a), diastolic blood pressure (b), body weight (c), food intake (d), and water intake (e) in groups of ND with vehicle, ND with CG, HFD with vehicle, and HFD with CG. Treatment with CG lowered systolic and diastolic blood pressure in the HFD-fed group gradually but did not affect body weight and consumption of food and water. (**p < 0.01, ***p < 0.001 vehicle-HFD vs. ND; ^##p < 0.01, ^###p < 0.001 CG-HFD vs. ND; ⁺p < 0.05 CG-ND vs. vehicle-ND; ^&p < 0.05, ^&&p < 0.01, ^&&&p < 0.001 CG-HFD vs. vehicle-HFD). Results are expressed as the mean ± SE (n = 5–8 mice per group). ND, normal diet; HFD, high-fat diet; Veh, vehicle; CG, CG200745

Fig. 3

Effect of CG200745 on HDAC activity in the kidney of ND- and HFD-fed mice. Graphs summarize kidney HDAC activity and mRNA expressions of HDAC 1, 2, 3, and 6. HDAC activities were increased by HFD and reversed by CG200745 to the ND level. mRNA expressions of HDAC 1, 2, 3, and 6 were increased by HFD but not decreased by CG200745. Results are expressed as the mean ± SE (n = 5–8 mice per group). HDAC, histone deacetylase; ND, normal diet; HFD, high-fat diet; Veh, vehicle; CG, CG200745

Fig. 4

Effect of CG200745 on renin-angiotensin system in the ND- or HFD-fed mice. Graphs summarize kidney mRNA expression of angiotensinogen (a), protein expression of angiotensinogen and representative picture of western blot (b), serum concentration of Ang II (c), kidney mRNA expression of renin (d), lung mRNA expression of ACE (e). a–e Renin-angiotensin system components were increased by HFD and reversed to the normal level by CG200745 treatment. Results are expressed as the mean ± SE (n = 3–5 mice per group). ND, normal diet; HFD, high-fat diet; Veh, vehicle; CG, CG200745; Ang II, angiotensin II; ACE, angiotensin-converting enzyme

Fig. 5

Effect of CG200745 on vascular contraction. Representative picture of western blot for phosphorylated MLC₂₀ at Thr18 and Ser19, phosphorylated MYPT1 at Thr853, and internal control beta-actin. Graphs summarize p-MYPT1 (a) and p-MLC₂₀ (b) in the mesenteric artery of ND and HFD-fed mice with/without CG200745 treatment. p-MYPT1 and p-MLC₂₀ were increased by HFD. CG200745 decreased phosphorylation of MYPT1 and MLC₂₀. Data are presented as the mean ± SE (n = 3–5 mice per group). p-, phosphorylated; MYPT1, Myosin phosphatase-targeting subunit1; MLC₂₀, myosin light chain 20; ND, normal diet; HFD, high-fat diet; Veh, vehicle; CG, CG200745