title: Structure-activity relationship of resveratrol and its analogue, 4,4'-dihydroxy-trans-stilbene, toward the endothelin axis in human endothelial cells.
abstract: Resveratrol inhibits endothelin-1, a vascular tension regulator. We synthesized the resveratrol analogue 4,4'-dihydroxy-trans-stilbene with 2 hydroxyl groups in the 4 and 4' position to obtain a molecule more active than resveratrol (3,4',5-trihydroxy-trans-stilbene). The results demonstrate that 4,4'-dihydroxy-trans-stilbene led to a significant decrease in total endothelin-1 secretion and in endothelin-1 messenger RNA (mRNA) levels in human endothelial cells. In addition, resveratrol and its analogue decreased endothelin-converting enzyme-1 mRNA levels and further reduced the activity of the enzyme. 4,4'-dihydroxy-trans-stilbene was more active than resveratrol because the new molecule exerted greater activity at the level of endothelin synthesis and conversion, even at a lower concentration. Although 4,4'-dihydroxy-trans-stilbene and resveratrol inhibited formation of reactive oxygen species and lipid peroxidation, the treatment of cells with different oxidant agents did not modify the endothelin-1 release. This finding suggests that the inhibition of endothelin-1 secretion is independent of the antioxidant properties of the 2 compounds. On the basis of these results, the resveratrol analogue 4,4'-dihydroxy-trans-stilbene could be a promising chemopreventive agent against cardiovascular diseases.
authors.affiliation: Department of Experimental Medicine, Section of General Pathology, University of Pavia, Pavia, Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Coppa
authors.forename: Maria Claudia
authors.initials: MC
authors.lastname: Lazzè
authors.forename: Ornella
authors.initials: O
authors.lastname: Cazzalini
authors.forename: Paola
authors.initials: P
authors.lastname: Perucca
authors.forename: Roberto
authors.initials: R
authors.lastname: Pizzala
authors.forename: Livia
authors.initials: L
authors.lastname: Bianchi
authors.forename: Lucia Anna
authors.initials: LA
authors.lastname: Stivala
authors.forename: Luca
authors.initials: L
authors.lastname: Forti
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccario
authors.forename: Vanio
authors.initials: V
authors.lastname: Vannini
authors.forename: Monica
authors.initials: M
authors.lastname: Savio
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D019332:Endothelin-1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013267:Stilbenes; C010118:4,4'-dihydroxystilbene; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes; D000077185:Resveratrol