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MBC in Press, published online ahead of print July 5, 2006
Mol. Biol. Cell 10.1091/mbc.E06-04-0353

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Submitted on April 25, 2006
Revised on June 7, 2006
Accepted on June 23, 2006

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

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

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

Monitoring Editor: Martin A. Schwartz

Regulation of gene transcription in vascular smooth muscle cells (VSMC) 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) 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 pairs 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 insights into the regulation of smMLCK expression at the molecular level and demonstrate the importance of SRF in regulating smMLCK promoter activity in SHR.

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




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