Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-γ Activators

Abstract

Background-Peroxisome proliferator-activated receptor-␥ (PPAR␥) is expressed in atherosclerotic plaques and in endothelial cells. The possible effects of PPAR␥ activators on endothelial activation and inflammatory response within the plaque are currently unknown. Methods and Results-We tested the hypothesis that PPAR␥ activators inhibit vascular cell adhesion molecule 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 PPAR␥ agonists troglitazone at 100 mol/L and 15-deoxy-⌬12,14 -prostaglandin J 2 (15d-PGJ2) at 20 mol/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 mol/L 15d-PGJ2 and 20 mol/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 (236Ϯ77 versus 177Ϯ43 macrophages, Pϭ0.03); an even more striking inhibition was found at 3200 mg/kg troglitazone (344Ϯ76 versus 172Ϯ83 macrophages, Pϭ0.005). Conclusions-PPAR␥

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

“…[6][7][8]. Consistent with these findings, certain omega 3 FA inhibited leukocyte adhesion in vivo in WT but not in PPAR␣-deficient (PPAR␣ Ϫ/Ϫ ) mice (9).…”

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

“…(C) Representative photographs of atherosclerosis in the aorta of apoE Ϫ͞Ϫ mice, a relevant section from an untreated apoE Ϫ͞Ϫ mouse (control), and an equivalent section of an apoE-deficient mouse after receiving GW2331 (PPAR␣͞␥ coagonist) or LG100364 (RXR agonist). production of matrix metalloproteinases (14), vascular cell adhesion molecule, and intercellular adhesion molecule (19). Furthermore, PPAR␥ agonists are reported to inhibit migration of vascular smooth muscle cells (20) as well as monocyte͞ macrophage homing (19) to atherosclerotic plaques.…”

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

“…Here we show that PPAR␥-RXR agonists inhibit parasite-induced TNF-␣ secretion by monocytes and THP-1 cells. PPAR␥ agonists have also been shown to inhibit TNF-␣-induced ICAM-1 expression (64). Collectively, these observations have clinical implications and suggest that adjunctive therapy with PPAR␥-RXR agonists might reduce excessive or unbalanced proinflammatory responses to infection and might inhibit the up-regulation of endothelial cell receptors associated with severe malaria.…”