Published Online
on October 13, 2003

A more recent version of this article appeared on November 1, 2003

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Submitted on December 30, 2002
Revised on January 21, 2003

Effect of Shear Stress on Asymmetric Dimethylarginine Release From Vascular Endothelial Cells

Tomohiro Osanai^*; Masayuki Saitoh; Satoko Sasaki; Hirofumi Tomita; Toshiro Matsunaga; and Ken Okumura

From the Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan.

^* To whom correspondence should be addressed. E-mail: osanait{at}cc.hirosaki-u.ac.jp.

Abstract--We demonstrated recently that plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, are increased by high salt intake concomitantly with a decrease in plasma levels of NO in human hypertension. We investigated the effect of shear stress on ADMA release in 2 types of cells: transformed human umbilical vein endothelial cells (HUVECs; cell line ECV-304) and HUVECs. Exposure of ECV-304 cells and HUVECs to shear stress with the use of a cone-plate viscometer enhanced gene expression of protein arginine methyltransferase (PRMT-1), ADMA synthase. In HUVECs, the ratio of PRMT-1 to glyceraldehyde 3-phosphate dehydrogenase mRNA was increased by 2-fold by a shear stress of 15 dyne/cm². A dominant-negative mutant of IB kinase and troglitazone at 8 µmol/L, an activator of peroxisome proliferator-activated receptor , abolished the shear stress-induced increase in PRMT-1 gene expression in parallel with the blockade of nuclear factor (NF)-B translocation into the nucleus. The activity of dimethylarginine dimethylaminohydrolase, the degradation enzyme of ADMA, was unchanged after shear stress 15 dyne/cm² and was enhanced by 1.48±0.06-fold (P<0.05) by shear stress at 25 dyne/cm². The release of ADMA was increased by 1.64±0.10-fold (P<0.05) by shear stress at 15 dyne/cm² but was not affected by shear stress at 25 dyne/cm². These results indicate that shear stress enhances gene expression of PRMT-1 and ADMA release via activation of the NF-B pathway. Shear stress at higher magnitudes facilitates the degradation of ADMA, thus returning ADMA release levels to baseline.

Key words: stress, mechanical • endothelium • gene expression • arginine • nitric oxide • nitric oxide synthase

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