title: P300/CBP associated factor regulates nitroglycerin-dependent arterial relaxation by N(ε)-lysine acetylation of contractile proteins.
abstract: OBJECTIVE
  To address the role of epigenetic enzymes in the process of arterial vasorelaxation and nitrate tolerance, in vitro and in vivo experiments were performed in the presence or absence of glyceryl trinitrate (GTN) or histone deacetylases/histone acetylases modulators.
  
  
  RESULTS
  In vitro single GTN administration rapidly increased cGMP synthesis and protein N(ε)-lysine acetylation in rat smooth muscle cells, including myosin light chain and smooth muscle actin. This phenomenon determined a decrease in myosin light chain phosphorylation and actomyosin formation. These effects were abolished by prolonged exposure to GTN and rescued by treatment with trichostatin A. In vivo, adult male rats were treated for 72 hours with subcutaneous injections of GTN alone or in combination with the histone deacetylases inhibitors trichostatin A, suberoylanilide hydroxamic acid, MS-27-275, or valproic acid. Ex vivo experiments performed on aortic rings showed that the effect of tolerance was reversed by all proacetylation drugs, including the p300/CREB binding protein-associated factor activator pentadecylidenemalonate 1b (SPV106). Any response to GTN was abolished by anacardic acid, a potent histone acetylases inhibitor.
  
  
  CONCLUSIONS
  This study establishes the following points: (1) GTN treatment increases histone acetylases activity; (2) GTN-activated p300/CREB binding protein-associated factor increases protein N(ε)-lysine acetylation; (3) N(ε)-lysine acetylation of contractile proteins influences GTN-dependent vascular response. Hence, combination of epigenetic drugs and nitroglycerin may be envisaged as a novel treatment strategy for coronary artery disease symptoms and other cardiovascular accidents of ischemic origin.
authors.affiliation: Laboratorio di PatologiaVascolare, Istituto Dermopatico dell’Immacolata, Roma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Colussi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Scopece
authors.forename: Serena
authors.initials: S
authors.lastname: Vitale
authors.forename: Francesco
authors.initials: F
authors.lastname: Spallotta
authors.forename: Stefania
authors.initials: S
authors.lastname: Mattiussi
authors.forename: Jessica
authors.initials: J
authors.lastname: Rosati
authors.forename: Barbara
authors.initials: B
authors.lastname: Illi
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
mesh_terms: D000107:Acetylation; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008239:Lysine / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D018994:Myosin Light Chains / Q000378:metabolism*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000199:Actins; D001549:Benzamides; D006152:Cyclic GMP; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008239:Lysine; D018994:Myosin Light Chains; D005996:Nitroglycerin; D011725:Pyridines; D014635:Valproic Acid; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C498862:Acta2 protein, rat; C118739:entinostat; C012589:trichostatin A