Exp Mol Med.  2010 Jul;42(7):524-532. 10.3858/emm.2010.42.7.053.

Piceatannol-3'-O-beta-D-glucopyranoside as an active component of rhubarb activates endothelial nitric oxide synthase through inhibition of arginase activity

• Woo A
• Min B
• Ryoo S

• KMID: 1104212
• DOI: http://doi.org/10.3858/emm.2010.42.7.053

Abstract

Arginase competitively inhibits nitric oxide synthase (NOS) via use of the common substrate L-arginine. Arginase II has recently reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. Here, we demonstrate that piceatannol-3'-O-beta-D-glucopyranoside (PG), a potent component of stilbenes, inhibits the activity of arginase I and II prepared from mouse liver and kidney lysates, respectively, in a dose-dependent manner. In human umbilical vein endothelial cells, incubation of PG markedly blocked arginase activity and increased NOx production, as measured by Griess assay. The PG effect was associated with increase of eNOS dimer ratio, although the protein levels of arginase II or eNOS were not changed. Furthermore, isolated mice aortic rings treated with PG showed inhibited arginase activity that resulted in increased nitric oxide (NO) production upto 78%, as measured using 4-amino-5-methylamino-2',7'-difluorescein (DAF-FM) and a decreased superoxide anions up to 63%, as measured using dihydroethidine (DHE) in the intact endothelium. PG showed IC50 value of 11.22 microM and 11.06 microM against arginase I and II, respectively. PG as an arginase inhibitor, therefore, represents a novel molecule for the therapy of cardiovascular diseases derived from endothelial dysfunction and may be used for the design of pharmaceutical compounds.

Keyword

arginase; endothelium, vascular; nitric oxide synthase type III; superoxides; 3,3',4,5'-tetrahydroxystilbene

MeSH Terms

Animals
Aorta/drug effects/metabolism
Arginase/*antagonists & inhibitors/metabolism
Dose-Response Relationship, Drug
Endothelial Cells/drug effects/enzymology
Enzyme Activation/drug effects
Glucosides/chemistry/*pharmacology
Humans
Mice
Mice, Inbred C57BL
Nitrates/metabolism
Nitric Oxide/biosynthesis
Nitric Oxide Synthase Type III/*metabolism
Nitrites/metabolism
Reactive Oxygen Species/metabolism
Rheum/*chemistry
Stilbenes/chemistry/*pharmacology