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PLoS One. 2019 Mar 4;14(3):e0213186. doi: 10.1371/journal.pone.0213186. eCollection 2019.

Class I histone deacetylase inhibitor MS-275 attenuates vasoconstriction and inflammation in angiotensin II-induced hypertension.

Ryu Y1,2, Kee HJ1,2, Sun S1,2,3,4, Seok YM5, Choi SY1,2,3, Kim GR1,2, Kee SJ6, Pflieger M7, Kurz T7, Kim HS8, Jeong MH1,2.

Author information

Heart Research Center of Chonnam National University Hospital, Gwangju, Republic of Korea.
Hypertension Heart Failure Research Center, Chonnam National University Hospital, Gwangju, Republic of Korea.
Molecular Medicine, Brain Korea 21 Plus, Chonnam National University Graduate School, Gwangju, Republic of Korea.
Zhoushan Hospital, Zhejiang University School of Medicine, Lincheng New District Zhoushan Zhejiang, China.
National Development Institute of Korean Medicine, Hwarang-ro, Gyeongsan-si, Gyeongsangbuk-do, Republic of Korea.
Department of Laboratory Medicine, Chonnam National University, Medical School and Hospital, Gwangju, Republic of Korea.
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr, 1, Düsseldorf, Germany.
Department of Forsensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.



Non-selective histone deacetylase (HDAC) inhibitors are known to improve hypertension. Here, we investigated the therapeutic effect and regulatory mechanism of the class I HDAC selective inhibitors, MS-275 and RGFP966, in angiotensin (Ang) II-induced hypertensive mice.


MS-275 inhibited the activity of HDAC1, HDAC2, and HDAC3, while RGFP966 weakly inhibited that of HDAC3 in a cell-free system. MS-275 and RGFP966 treatment reduced systolic blood pressure and thickness of the aorta wall in Ang II-induced hypertensive mice. MS-275 treatment reduced aorta collagen deposition, as determined by Masson's trichrome staining. MS-275 decreased the components of the renin angiotensin system and increased vascular relaxation of rat aortic rings via the nitric oxide (NO) pathway. NO levels reduced by Ang II were restored by MS-275 treatment in vascular smooth muscle cells (VSMCs). However, MS-275 dose (3 mg·kg-1·day-1) was not enough to induce NO production in vivo. In addition, MS-275 did not prevent endothelial nitric oxide synthase (eNOS) uncoupling in the aorta of Ang II-induced mice. Treatment with MS-275 failed to inhibit Ang II-induced expression of NADPH oxidase (Nox)1, Nox2, and p47phox. MS-275 treatment reduced proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and monocyte chemoattractant protein (MCP)-1, as well as adhesion molecules. Histological analysis showed that Ang II-induced macrophage infiltration was reduced by MS-275 and RGFP966 administration.


Our results indicate that class I HDAC selective inhibitors may be good therapeutic agents for the treatment of hypertension through the regulation of vascular remodeling and vasoconstriction, as well as inflammation.

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