title: Histone deacetylase 8 regulates cortactin deacetylation and contraction in smooth muscle tissues.
abstract: Histone deacetylases (HDACs) are a family of enzymes that mediate nucleosomal histone deacetylation and gene expression. Some members of the HDAC family have also been implicated in nonhistone protein deacetylation, which modulates cell-cycle control, differentiation, and cell migration. However, the role of HDACs in smooth muscle contraction is largely unknown. Here, HDAC8 was localized both in the cytoplasm and the nucleus of mouse and human smooth muscle cells. Knockdown of HDAC8 by lentivirus-encoding HDAC8 shRNA inhibited force development in response to acetylcholine. Treatment of smooth muscle tissues with HDAC8 inhibitor XXIV (OSU-HDAC-44) induced relaxation of precontracted smooth muscle tissues. In addition, cortactin is an actin-regulatory protein that undergoes deacetylation during migration of NIH 3T3 cells. In this study, acetylcholine stimulation induced cortactin deacetylation in mouse and human smooth muscle tissues, as evidenced by immunoblot analysis using antibody against acetylated lysine. Knockdown of HDAC8 by RNAi or treatment with the inhibitor attenuated cortactin deacetylation and actin polymerization without affecting myosin activation. Furthermore, expression of a charge-neutralizing cortactin mutant inhibited contraction and actin dynamics during contractile activation. These results suggest a novel mechanism for the regulation of smooth muscle contraction. In response to contractile stimulation, HDAC8 may mediate cortactin deacetylation, which subsequently promotes actin filament polymerization and smooth muscle contraction.
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; and.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; and.
authors.forename: Shu
authors.initials: S
authors.lastname: Chen
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; and.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Cleary
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; and.
authors.forename: Ruping
authors.initials: R
authors.lastname: Wang
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; and.
authors.forename: Olivia J
authors.initials: OJ
authors.lastname: Gannon
authors.affiliation: Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; and tangd@mail.amc.edu.
authors.forename: Dale D
authors.initials: DD
authors.lastname: Tang
mesh_terms: D000107:Acetylation; D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D051356:Cortactin / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics* / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009218:Myosins / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000493:pharmacokinetics
chemical_list: C555920:4-(2,2-dimethyl-4-phenylbutyrylamino)-N-hydroxybenzamide; D001549:Benzamides; D051356:Cortactin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D009218:Myosins
keywords: actin; histone deacetylase; muscle contraction; protein acetylation; smooth muscle