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Vol. 17, Issue 9, 4039-4050, September 2006

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Increased Myosin Light Chain Kinase Expression in Hypertension: Regulation by Serum Response Factor via an Insertion Mutation in the Promoter

Yoo-Jeong Han^*, Wen-Yang Hu^*, Olga Chernaya^*, Nenad Antic^*, Lianzhi Gu^*, Mahesh Gupta, Mariann Piano, and Primal de Lanerolle^*

*Department of Physiology and Biophysics, College of Medicine, and Department of Medical and Surgical Nursing, College of Nursing, University of Illinois at Chicago, Chicago, IL 60612; and Department of Surgery, University of Chicago, Chicago, IL 60637

Submitted April 25, 2006; Revised June 7, 2006; Accepted June 23, 2006
Monitoring Editor: Martin A. Schwartz

Regulation of gene transcription in vascular smooth muscle cells (VSMCs) by serum response factor (SRF) plays a crucial role in vascular development and in the pathophysiology of vascular diseases. Nevertheless, the regulation of specific genes by SRF in vascular diseases is poorly understood. Therefore, we investigated the regulation of smooth muscle myosin light chain kinase (smMLCK) by using spontaneously hypertensive rats (SHR) as an experimental model. We found that smMLCK expression in blood vessels increases during the development of hypertension and is always greater in blood vessels from SHR compared with normotensive rats. Analysis of the DNA sequences of the promoters isolated from SHR and normotensive rats revealed that SHR contain a 12-base pair insertion adjacent to the CArG box. This insertion increases SRF binding to the CArG box and positively regulates SRF-dependent promoter activity. The increase in smMLCK expression was blocked by dominant-negative SRF, dominant-negative Ras, or antisense oligonucleotides to ERK. In vivo, inhibiting MEK decreased smMLCK expression and blood pressure in SHR partly by decreasing SRF binding to the smMLCK promoter. These data provide novel insight into the regulation of smMLCK expression at the molecular level and demonstrate the importance of SRF in regulating smMLCK promoter activity in SHR.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-04-0353) on July 5, 2006.

Address correspondence to: Primal de Lanerolle (primal{at}uic.edu)

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