Abstract
Endothelial arginase constrains the activity of endothelial nitric oxide synthase
by reducing nitric oxide bioavailability, which contributes to vascular diseases.
During screening, we identified a novel compound from the rhizome of Polygonum multiflorum (Polygonaceae), 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), which inhibited arginase activity. THSG exhibited noncompetitive
inhibition of arginase II and inhibited both arginases I and II in a dose-dependent
manner. THSG-dependent arginase inhibition reciprocally increased nitric oxide production
and decreased reactive oxygen species generation in aortic endothelia. These effects
were associated with increased dimerization of endothelial nitric oxide synthase without
changes in the protein expression levels of arginase I, arginase II, or endothelial
nitric oxide synthase. In vascular tension assays, when aortic vessels from wild-type
mice are incubated with THSG, responses to the nitric oxide-dependent vasorelaxant
acetylcholine were augmented, but responses to an nitric oxide donor, sodium nitroprusside,
were not affected. On the other hand, phenylephrine-dependent vasoconstriction was
significantly retarded in THSG-treated vessels. In a high-cholesterol diet-fed atherogenic
model mice (ApoE-/-), THSG improved endothelial function by enhancement of the nitric oxide-cGMP pathway.
Taken together, these results suggest that THSG may exert vasoprotective effects through
augmentation of nitric oxide signaling by inhibiting arginase. Therefore, THSG may
be useful in the treatment of vascular diseases that are derived from endothelial
dysfunction, such as atherosclerosis.
Key words
Polygonum multiflorum
- Polygonaceae - 2,3,5,4′-tetrahydroxystilbene-2-
O-
β-D-glucoside - arginase - endothelial nitric oxide synthase - superoxide - vascular
function
