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


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.
Sahar
Saurabh
S
Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
Reddy
Marpadga A
MA
Wong
Cynthie
C
Meng
Li
L
Wang
Mei
M
Natarajan
Rama
R
D000107:Acetylation; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000378:metabolism*
D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D014157:Transcription Factors; D000804:Angiotensin II; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1