Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells

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 greater than or equal to 15 dyne/cm(2). A dominant- negative mutant of IkappaB kinase alpha and troglitazone at 8 mumol/L, an activator of peroxisome proliferator - activated receptor gamma, abolished the shear stress - induced increase in PRMT-1 gene expression in parallel with the blockade of nuclear factor (NF)-kappaB translocation into the nucleus. The activity of dimethylarginine dimethylaminohydrolase, the degradation enzyme of ADMA, was unchanged after shear stress greater than or equal to 15 dyne/cm(2) and was enhanced by 1.48 +/- 0.06-fold (P < 0.05) by shear stress at 25 dyne/cm(2). The release of ADMA was increased by 1.64 +/- 0.10-fold ( P < 0.05) by shear stress at 15 dyne/cm(2) but was not affected by shear stress at 25 dyne/cm(2). These results indicate that shear stress enhances gene expression of PRMT-1 and ADMA release via activation of the NF-kappaB pathway. Shear stress at higher magnitudes facilitates the degradation of ADMA, thus returning ADMA release levels to baseline.