Histone Deacetylase Inhibitors Relax Mouse Aorta Partly through Their Inhibitory Action on L-Type Ca2+ Channels

Changbo Zheng; Mingkui Zhong; Zenghua Qi; Fan Shen; Qiannan Zhao; Lulu Wu; Yu Huang; Suk-Ying Tsang; Xiaoqiang Yao

doi:10.1124/jpet.117.242685

Histone Deacetylase Inhibitors Relax Mouse Aorta Partly through Their Inhibitory Action on L-Type Ca²⁺ Channels

J Pharmacol Exp Ther. 2017 Nov;363(2):211-220. doi: 10.1124/jpet.117.242685. Epub 2017 Aug 31.

Authors

Changbo Zheng¹, Mingkui Zhong², Zenghua Qi¹, Fan Shen¹, Qiannan Zhao¹, Lulu Wu¹, Yu Huang¹, Suk-Ying Tsang¹, Xiaoqiang Yao²

Affiliations

¹ Department of Physiology, Anhui Medical University, Hefei, China (M.Z., F.S.); School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, China (C.Z.); and School of Biomedical Sciences and Li Ka Shing Institute of Health Science (C.Z., Q.Z., L.W., Y.H., X.Y.), School of Life Sciences (S.-Y.T, Z.Q.), Shenzhen Research Institute (C.Z., Q.Z., L.W., X.Y.), The Chinese University of Hong Kong, Shenzhen, China.
² Department of Physiology, Anhui Medical University, Hefei, China (M.Z., F.S.); School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, China (C.Z.); and School of Biomedical Sciences and Li Ka Shing Institute of Health Science (C.Z., Q.Z., L.W., Y.H., X.Y.), School of Life Sciences (S.-Y.T, Z.Q.), Shenzhen Research Institute (C.Z., Q.Z., L.W., X.Y.), The Chinese University of Hong Kong, Shenzhen, China. mingkuizhong@ahmu.edu.cn yao2068@cuhk.edu.hk.

PMID: 28860353
DOI: 10.1124/jpet.117.242685

Abstract

Histone deacetylase (HDAC) inhibitors modulate acetylation/deacetylation of histone and nonhistone proteins. They have been widely used for cancer treatment. However, there have been only a few studies investigating the effect of HDAC inhibitors on vascular tone regulation, most of which employed chronic treatment with HDAC inhibitors. In the present study, we found that two hydroxamate-based pan-HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), could partially but acutely relax high extracellular K⁺-contracted mouse aortas. SAHA and TSA also attenuated the high extracellular K⁺-induced cytosolic Ca²⁺ rise and inhibited L-type Ca²⁺ channel current in whole-cell patch-clamp. These data demonstrate that SAHA could inhibit L-type Ca²⁺ channels to cause vascular relaxation. In addition, SAHA and TSA dose dependently relaxed the arteries precontracted with phenylephrine. The relaxant effect of SAHA and TSA was greater in phenylephrine-precontracted arteries than in high K⁺-contracted arteries. Although part of the relaxant effect of SAHA and TSA on phenylephrine-precontracted arteries was related to L-type Ca²⁺ channels, both agents could also induce relaxation via a mechanism independent of L-type Ca²⁺ channels. Taken together, HDAC inhibitors SAHA and TSA can acutely relax blood vessels via their inhibitory action on L-type Ca²⁺ channels and via another L-type Ca²⁺ channel-independent mechanism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta / drug effects*
Aorta / metabolism
Aorta / physiology*
Biological Transport / drug effects
Calcium / metabolism
Calcium Channels, L-Type / metabolism*
Cytosol / drug effects
Cytosol / metabolism
Electrophysiological Phenomena / drug effects
Extracellular Space / drug effects
Extracellular Space / metabolism
Histone Deacetylase Inhibitors / pharmacology*
Hydroxamic Acids / pharmacology*
Male
Mice
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / metabolism
Phenylephrine / pharmacology
Potassium / metabolism
Vasodilation / drug effects*
Vorinostat

Substances

Calcium Channels, L-Type
Histone Deacetylase Inhibitors
Hydroxamic Acids
Phenylephrine
trichostatin A
Vorinostat
Potassium
Calcium