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Laminar shear stress (LSS) due to pulsatile blood flow
enhances endothelial function by multiple mechanisms including NO production.
Red wine and its constituent, resveratrol, have also been postulated to provide
vascular protective effects. The aim of the present study was to compare the
effects of mechanical LSS and pharmacological resveratrol treatments on the
endothelial citrulline-NO cycle. Human umbilical vein endothelial cells
(HUVECs) were treated with LSS (12 dyn·cm-2) or resveratrol (25 - 100
μM). The expressions of argininosuccinate synthetase 1 (ASS1),
argininosuccinate lyase (ASL), nitric oxide synthase 3 (NOS3) and cationic
amino acid transporter 1 (CAT1), and the production of NO were determined.
The expressions of Kruppel-like factor (KLF) 2 and KLF4 as upstream regulators
of ASS1 and NOS3 were also analyzed. LSS strongly increased the mRNA levels of
ASS1 (8.3 fold) and NOS3 (5.4 fold) without significant effects on ASL and CAT1
mRNAs. Resveratrol increased the ASS1 mRNA level in a dose-dependent manner up
to 3.8 fold at 100 μM. The effects of resveratrol on the expressions of KLF2
and KLF4 mRNAs were smaller than those of LSS. Protein levels of ASS1 and NOS3, and NO production were markedly increased
by LSS but resveratrol (50 μM) increased only ASS1 protein level. The results
of the current study showed that LSS had greater effects on the citrulline-NO
cycle activity leading to NO production, compared to resveratrol. Because resveratrol was not so effective at stimulating the
endothelial citrulline-NO cycle, further
studies are needed to find more potent drugs that increase the expression of ASS1
and NOS3 genes.