Trans- but not cis-resveratrol impairs angiotensin-II-mediated vascular inflammation through inhibition of NF-κB activation and peroxisome proliferator-activated receptor-gamma upregulation.
Angiotensin II (Ang-II) displays inflammatory activity and is implicated in several cardiovascular disorders. This study evaluates the effect of cis- and trans (t)-resveratrol (RESV) in two in vivo models of vascular inflammation and identifies the cardioprotective mechanisms that underlie them. In vivo, Ang-II-induced arteriolar leukocyte adhesion was inhibited by 71% by t-RESV (2.1 mg/kg, i.v.), but was not affected by cis-RESV. Because estrogens influence the rennin-angiotensin system, chronic treatment with t-RESV (15 mg/kg/day, orally) inhibited ovariectomy-induced arteriolar leukocyte adhesion by 81%, partly through a reduction of cell adhesion molecule (CAM) expression and circulating levels of cytokine-induced neutrophil chemoattractant, MCP-1, and MIP-1alpha. In an in vitro flow chamber system, t-RESV (1-10 microM) undermined the adhesion of human leukocytes under physiological flow to Ang-II-activated human endothelial cells. These effects were accompanied by reductions in monocyte and endothelial CAM expression, chemokine release, phosphorylation of p38 MAPK, and phosphorylation of the p65 subunit of NF-kappaB. Interestingly, t-RESV increased the expression of peroxisome proliferator-activated receptor-gamma in human endothelial and mononuclear cells. These results demonstrate for the first time that the in vivo anti-inflammatory activity of RESV is produced by its t-RESV, which possibly interferes with signaling pathways that cause the upregulation of CAMs and chemokine release. Upregulation of proliferator-activated receptor-gamma also appears to be involved in the cardioprotective effects of t-RESV. In this way, chronic administration of t-RESV may reduce the systemic inflammatory response associated with the activation of the rennin-angiotensin system, thereby decreasing the risk of further cardiovascular disease.
Rius
Cristina
C
Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
Abu-Taha
May
M
Hermenegildo
Carlos
C
Piqueras
Laura
L
Cerda-Nicolas
Jose-Miguel
JM
Issekutz
Andrew C
AC
Estañ
Luís
L
Cortijo
Julio
J
Morcillo
Esteban J
EJ
Orallo
Francisco
F
Sanz
Maria-Jesus
MJ
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D002318:Cardiovascular Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010052:Ovariectomy; D047495:PPAR gamma / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013237:Stereoisomerism; D013267:Stilbenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D020533:Angiogenesis Inhibitors; D018836:Inflammation Mediators; D016328:NF-kappa B; D047495:PPAR gamma; D013267:Stilbenes; D000804:Angiotensin II; D000077185:Resveratrol