P300/CBP associated factor regulates nitroglycerin-dependent arterial relaxation by nε-lysine acetylation of contractile proteins

Claudia Colussi, Alessandro Scopece, Serena Vitale, Francesco Spallotta, Stefania Mattiussi, Jessica Rosati, Barbara Illi, Antonello Mai, Sabrina Castellano, Gianluca Sbardella, Antonella Farsetti, Maurizio C. Capogrossi, Carlo Gaetano

Research output: Contribution to journalArticle

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. METHODS AND RESULTS-: In vitro single GTN administration rapidly increased cGMP synthesis and protein N-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. CONCLUSION-: 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-lysine acetylation; (3) N-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.

Original languageEnglish
Pages (from-to)2435-2443
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number10
DOIs
Publication statusPublished - Nov 2012

Keywords

  • histone acetylases
  • histone deacetylases
  • nitroglycerin
  • protein acetylation
  • smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Colussi, C., Scopece, A., Vitale, S., Spallotta, F., Mattiussi, S., Rosati, J., Illi, B., Mai, A., Castellano, S., Sbardella, G., Farsetti, A., Capogrossi, M. C., & Gaetano, C. (2012). P300/CBP associated factor regulates nitroglycerin-dependent arterial relaxation by nε-lysine acetylation of contractile proteins. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(10), 2435-2443. https://doi.org/10.1161/ATVBAHA.112.254011