title: Ursolic acid from the Chinese herb danshen (Salvia miltiorrhiza L.) upregulates eNOS and downregulates Nox4 expression in human endothelial cells.
abstract: Danshen, the dried root of Salvia miltiorrhiza Bunge (Lamiaceae), is one of the most commonly used traditional Chinese medicines for cardiovascular indications. In EA.hy 926 cells, a cell line derived from human umbilical vein endothelial cells (HUVEC), an aqueous extract of danshen, and also a methanol extract of the plant, increased eNOS promoter activity, eNOS mRNA and protein expression, as well as endothelial NO production. A dichloromethane extract, in contrast, did not change eNOS gene expression. Thus, the active danshen constituent(s) responsible for eNOS upregulation is (are) hydrophilic and/or alcohol-soluble. One such compound is ursolic acid that significantly increased eNOS expression in EA.hy 926 cells and native HUVEC, and enhanced bioactive NO production measured in terms of its cGMP increasing activity. Other tested hydrophilic and alcohol-soluble compounds isolated from danshen had no effect on eNOS expression. Interestingly, ursolic acid also reduced the expression of the NADPH oxidase subunit Nox4 and suppressed the production of reactive oxygen species in human endothelial cells. Upregulation of eNOS and a parallel downregulation of Nox4 lead to an increase in bioactive NO. This in turn could mediate some of the beneficial effects of danshen. Ursolic acid is a prototypical compound responsible for this effect of the plant.
authors.affiliation: Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steinkamp-Fenske
authors.forename: Larissa
authors.initials: L
authors.lastname: Bollinger
authors.forename: Natalie
authors.initials: N
authors.lastname: Völler
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yao
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bauer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.forename: Huige
authors.initials: H
authors.lastname: Li
mesh_terms: D000438:Alcohols / Q000737:chemistry; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D000432:Methanol / Q000737:chemistry; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D018384:Oxidative Stress; D010936:Plant Extracts; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D014315:Triterpenes / Q000737:chemistry / Q000378:metabolism*; D000097245:Ursolic Acid
chemical_list: D000438:Alcohols; D000432:Methanol; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D052250:Nitric Oxide Synthase Type III; D010936:Plant Extracts; D012333:RNA, Messenger; D012260:Ribonucleases; D014315:Triterpenes; D000097245:Ursolic Acid; C498910:NOX4 protein, human