on May 10, 2007
Published online before print May 10, 2007, doi: 10.1161/ATVBAHA.107.145862
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Submitted on January 8, 2007
Accepted on April 23, 2007
Cooperation of SRC-1 and p300 With NF-
B and CREB in Angiotensin II-Induced IL-6 Expression in Vascular Smooth Muscle Cells
Sahar Saurabh ;
From the Graduate School of Biological Sciences (S.S., C.W., R.N.) and the Department of Diabetes (S.S., M.A.R., L.M., M.W., R.N.), Beckman Research Institute of City of Hope, Duarte, Calif.
* To whom correspondence should be addressed. E-mail: RNatarajan{at}coh.org.
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-
B 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-B (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-B 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.
Key words: angiotensin II • histone acetylation • IL-6 • NF-
B •
CREB •
SRC-1 •
CBP/p300 •
ERK •
vascular smooth muscle cells
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