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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1528.)
© 2007 American Heart Association, Inc.

Vascular Biology

Cooperation of SRC-1 and p300 With NF-B and CREB in Angiotensin II-Induced IL-6 Expression in Vascular Smooth Muscle Cells

Saurabh Sahar; Marpadga A. Reddy; Cynthie Wong; Li Meng; Mei Wang; Rama Natarajan

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.

Correspondence to Rama Natarajan, PhD, Professor, Department of Diabetes, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010. 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.

In vascular smooth muscle cells Angiotensin II-induced IL-6 expression involves histone H3 lysine acetylation mediated by histone acetyl transferases p300 and SRC-1 and their cooperation with transcription factors NF-B and CREB. ERK signaling plays a key role by regulating the activation of these transcription factors and histone acetyl transferases.

Key Words: angiotensin II • histone acetylation • IL-6 • NF-B • CREB • SRC-1 • CBP/p300 • ERK • vascular smooth muscle cells

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