Cooperation of SRC-1 and p300 with NF-kappaB and CREB in angiotensin II-induced IL-6 expression in vascular smooth muscle cells

Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1528-34. doi: 10.1161/ATVBAHA.107.145862. Epub 2007 May 10.

Abstract

Objective: The purpose of this study was to evaluate the role of coactivator histone acetyltransferases (HATs) p300 and SRC-1 in angiotensin II (Ang II)-induced interleukin-6 (IL-6) gene expression in vascular smooth muscle cells (VSMCs).

Methods and results: Ang II increased IL-6 mRNA expression via NF-kappaB and CREB in an extracellular signal-regulated kinase (ERK)-dependent manner in rat VSMCs. It was also significantly enhanced by the histone deacetylase inhibitor, Trichostatin A. Chromatin immunoprecipitation (ChIP) assays showed that Ang II increased Histone H3 Lysine (K9/14) acetylation on the IL-6 promoter. Ang II-induced IL-6 promoter transactivation was significantly enhanced by p300 and SRC-1, with maximal activation in cells cotransfected with NF-kappaB (p65) and SRC-1. Nucleofection of VSMCs with either an ERK phosphorylation site mutant of SRC-1 or p300/CBP HAT deficient mutants significantly blocked Ang II-induced IL-6 expression. ChIP assays revealed that Ang II enhanced coordinate occupancy of p65, CREB, p300, and SRC-1 at the IL-6 promoter. An ERK pathway inhibitor blocked Ang-induced IL-6 promoter SRC-1 occupancy and histone acetylation.

Conclusions: Ang II-induced IL-6 expression requires NF-kappaB and CREB as well as ERK-dependent histone acetylation mediated by p300 and SRC-1. These results provide new insights into nuclear chromatin mechanisms by which Ang II regulates inflammatory gene expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Angiotensin II / metabolism*
  • Angiotensin II / pharmacology
  • Animals
  • CREB-Binding Protein / metabolism*
  • Cells, Cultured
  • E1A-Associated p300 Protein / metabolism
  • Gene Expression Regulation
  • Histone Acetyltransferases / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Male
  • Models, Animal
  • Muscle, Smooth, Vascular / enzymology*
  • NF-kappa B / metabolism
  • Nuclear Receptor Coactivator 1
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sensitivity and Specificity
  • Transcription Factors / metabolism*

Substances

  • Interleukin-6
  • NF-kappa B
  • RNA, Messenger
  • Transcription Factors
  • Angiotensin II
  • CREB-Binding Protein
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1