title: Histone deacetylase 4 controls neointimal hyperplasia via stimulating proliferation and migration of vascular smooth muscle cells.
abstract: Histone deacetylases (HDACs) are transcriptional coregulators. Recently, we demonstrated that HDAC4, one of class IIa family members, promotes reactive oxygen species-dependent vascular smooth muscle inflammation and mediates development of hypertension in spontaneously hypertensive rats. Pathogenesis of hypertension is, in part, modulated by vascular structural remodeling via proliferation and migration of vascular smooth muscle cells (SMCs). Thus, we examined whether HDAC4 controls SMC proliferation and migration. In rat mesenteric arterial SMCs, small interfering RNA against HDAC4 inhibited platelet-derived growth factor (PDGF)-BB-induced SMC proliferation as determined by a cell counting and bromodeoxyuridine incorporation assay as well as migration as determined by Boyden chamber assay. Expression and activity of HDAC4 were increased by PDGF-BB. HDAC4 small interfering RNA inhibited phosphorylation of p38 mitogen-activated protein kinase and heat shock protein 27 and expression of cyclin D1 as measured by Western blotting. HDAC4 small interfering RNA also inhibited PDGF-BB-induced reactive oxygen species production as measured fluorometrically using 2', 7'-dichlorofluorescein diacetate and nicotinamide adenine dinucleotide phosphate oxidase activity as measured by lucigenin assay. A Ca(2+)/calmodulin-dependent protein kinase II inhibitor, KN93, inhibited PDGF-BB-induced SMC proliferation and migration as well as phosphorylation of HDAC4. In vivo, a class IIa HDACs inhibitor, MC1568 prevented neointimal hyperplasia in mice carotid ligation model. MC1568 also prevented increased activation of HDAC4 in the neointimal lesions. The present results for the first time demonstrate that HDAC4 controls PDGF-BB-induced SMC proliferation and migration through activation of p38 mitogen-activated protein kinase/heat shock protein 27 signals via reactive oxygen species generation in a Ca(2+)/calmodulin-dependent protein kinase-dependent manner, which may lead to the neointimal hyperplasia in vivo.
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35-1, Towada City, Aomori 034-8628, Japan. yamawaki@vmas.kitasato-u.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.forename: Tomoka
authors.initials: T
authors.lastname: Morita
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D061251:Primary Cell Culture; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D043925:Angiogenesis Inducing Agents; D004791:Enzyme Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D000077214:Becaplermin; C559944:HDAC4 protein, rat; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: hypertension; intercellular signaling peptides and proteins; muscle; reactive oxygen species; signal transduction; smooth