Department of Molecular Medicine and Medical Research Center, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu, 42601, Republic of Korea.
Department of Molecular Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Mar;393(3):491-500. doi: 10.1007/s00210-019-01749-5. Epub 2019 Oct 26.
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 (MLC) 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 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.
由于西式饮食的消费和缺乏运动，肥胖在全球范围内迅速增长。肥胖是高血压的主要危险因素之一。新型组蛋白去乙酰化酶（HDAC）抑制剂 CG200745 最初是为治疗各种癌症而开发的。先前的研究表明，CG200745 通过抑制去氧皮质酮醋酸盐诱导的高血压大鼠的心肌肥厚和纤维化来减轻高血压。本研究旨在探讨 CG200745 在高脂饮食（HFD）诱导的高血压中的作用及其潜在机制。将 9 周龄 C57BL/6 小鼠用正常饮食（ND）或 HFD 喂养 17 周。每组小鼠用腹腔注射给予载体或 CG200745 治疗 9 天。与 ND 组相比，HFD 组小鼠体重、血压（BP）、HDAC 活性、肾脏血管紧张素原和肾素表达、肺 ACE 表达、血清血管紧张素 II（Ang II）浓度和肠系膜动脉肌球蛋白轻链（MLC）磷酸化均升高。CG200745 降低了 HFD 组的 BP、HDAC 活性、肾脏中的肾素和血管紧张素原、肺中的 ACE、血清中的 Ang II 水平和 MLC 的磷酸化。总之，CG200745 通过抑制 HDAC/Ang II/血管收缩轴改善了 HFD 诱导的高血压。我们的结果为 CG200745 作为 HFD 诱导的高血压的一种新的治疗选择提供了依据。
