Open AccessHistone deacetylase inhibitors promote eNOS expression in vascular smooth muscle cells and suppress hypoxia‐induced cell growth
Author(s) -
Tan Xiaoling,
Feng Lan,
Huang Xiaoyong,
Yang Yidong,
Yang Chengzhong,
Gao Yuqi
Publication year - 2017
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13122
Subject(s) - enos , vascular smooth muscle , hypoxia (environmental) , gene knockdown , apoptosis , medicine , cell growth , biology , endocrinology , histone deacetylase , chemistry , nitric oxide synthase , nitric oxide , biochemistry , histone , organic chemistry , smooth muscle , oxygen , gene
Abstract Hypoxia stimulates excessive growth of vascular smooth muscle cells ( VSMC s) contributing to vascular remodelling. Recent studies have shown that histone deacetylase inhibitors ( HDI s) suppress VSMC proliferation and activate eNOS expression. However, the effects of HDI on hypoxia‐induced VSMC growth and the role of activated eNOS in VSMC s are unclear. Using an EdU incorporation assay and flow cytometry analysis, we found that the HDI s, butyrate (Bur) and suberoylanilide hydroxamic acid ( SAHA ) significantly suppressed the proliferation of hypoxic VSMC lines and induced apoptosis. Remarkable induction of cleaved caspase 3, p21 expression and reduction of PCNA expression were also observed. Increased eNOS expression and enhanced NO secretion by hypoxic VSMC lines were detected using Bur or SAHA treatment. Knockdown of eNOS by si RNA transfection or exposure of hypoxic VSMC s to NO scavengers weakened the effects of Bur and SAHA on the growth of hypoxic VSMC s. In animal experiments, administration of Bur to Wistar rats exposed to hypobaric hypoxia for 28 days ameliorated the thickness and collagen deposition in pulmonary artery walls. Although the mean pulmonary arterial pressure ( mPAP ) was not obviously decreased with Bur in hypoxic rats, right ventricle hypertrophy index ( RVHI ) was decreased and the oxygen partial pressure of arterial blood was elevated. Furthermore, cell viability was decreased and eNOS and cleaved caspase 3 were induced in HDI ‐treated rat pulmonary arterial SMC s. These findings imply that HDI s prevent hypoxia‐induced VSMC growth, in correlation with activated eNOS expression and activity in hypoxic VSMCs.