title: Histone deacetylase inhibitors promote eNOS expression in vascular smooth muscle cells and suppress hypoxia-induced cell growth.
abstract: Hypoxia stimulates excessive growth of vascular smooth muscle cells (VSMCs) contributing to vascular remodelling. Recent studies have shown that histone deacetylase inhibitors (HDIs) suppress VSMC proliferation and activate eNOS expression. However, the effects of HDI on hypoxia-induced VSMC growth and the role of activated eNOS in VSMCs are unclear. Using an EdU incorporation assay and flow cytometry analysis, we found that the HDIs, 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 siRNA transfection or exposure of hypoxic VSMCs to NO scavengers weakened the effects of Bur and SAHA on the growth of hypoxic VSMCs. 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 SMCs. These findings imply that HDIs prevent hypoxia-induced VSMC growth, in correlation with activated eNOS expression and activity in hypoxic VSMCs.
authors.affiliation: Department of High Altitude Physiology & Biology, College of High Altitude Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of High Altitude Physiology & Biology, College of High Altitude Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Feng
authors.affiliation: Southwest Eye Hospital, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology & High Altitude Pathology, College of High Altitude Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of High Altitude Physiology & Biology, College of High Altitude Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Chengzhong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology & High Altitude Pathology, College of High Altitude Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D000860:Hypoxia / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects; D017208:Rats, Wistar; D066253:Vascular Remodeling / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D001565:Benzoates; D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007093:Imidazoles; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D000077337:Vorinostat; D052250:Nitric Oxide Synthase Type III
keywords: endothelial nitric oxide synthase; histone deacetylase inhibitor; hypoxia; vascular remodelling; vascular smooth muscle cell