Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators.
BACKGROUND
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPARgamma activators on endothelial activation and inflammatory response within the plaque are currently unknown.


RESULTS
We tested the hypothesis that PPARgamma activators inhibit vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1) expression in cultured endothelial cells (evaluated by flow cytometry) and homing of monocyte/macrophages to atherosclerotic plaques in vivo. In endothelial cells, the PPARgamma agonists troglitazone at 100 micromol/L and 15-deoxy-(Delta12,14)-prostaglandin J(2) (15d-PGJ2) at 20 micromol/L markedly attenuated the tumor necrosis factor-induced expression of VCAM-1 and ICAM-1. A significant inhibition of VCAM-1 expression was also evident at 5 and 10 micromol/L 15d-PGJ2 and 20 micromol/L troglitazone. Expression of E-selectin and PECAM-1 was not altered. To confirm the biological relevance of these results, we assessed the effects of troglitazone on monocyte/macrophage homing to atherosclerotic plaques in apoE-deficient mice. A 7-day treatment with troglitazone (400 mg/kg) significantly reduced monocyte/macrophage homing to atherosclerotic plaques (236+/-77 versus 177+/-43 macrophages, P=0.03); an even more striking inhibition was found at 3200 mg/kg troglitazone (344+/-76 versus 172+/-83 macrophages, P=0.005).


CONCLUSIONS
PPARgamma activators inhibit expression of VCAM-1 and ICAM-1 in activated endothelial cells and significantly reduce monocyte/macrophage homing to atherosclerotic plaques. These findings suggest that PPARgamma activators, currently used in treatment of type II diabetes, may have beneficial effects in modulating inflammatory response in atherosclerosis.
Pasceri
V
V
Department of Internal Medicine, Institute of Molecular Medicine for the Prevention of Human Diseases University of Texas Health Science Center, Houston, Texas, USA.
Wu
H D
HD
Willerson
J T
JT
Yeh
E T
ET
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects*; D000077288:Troglitazone; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000502:physiology*; D014657:Vasculitis / Q000188:drug therapy*
D002839:Chromans; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000077288:Troglitazone