Irbesartan administration therapeutically influences circulating endothelial progenitor cell and microparticle mobilization by involvement of pro-inflammatory cytokines

Abstract

Circulating microparticles (MPs) and endothelial progenitor cells (EPCs) correlate with endothelial dysfunction and contribute to the pathogenesis of atherosclerosis. In this context, we explored whether the angiotensin II type I receptor antagonist, irbesartan, exerts a pharmacological control in the atherosclerotic process by the improvement of EPC mobilization and inhibitory effects on MP release and VEGF and SDF-1α levels in the hypertensive-hypercholesterolemic (HH) hamster model. The HH hamsters were treated with irbesartan (50mg/kg b.w/day administered by gavage) for 4 month (HHI). We analyzed MP/EPC infiltration in vascular wall before and after irbesartan administration as well as the endothelial function and expression of VEGF/SDF-1α in plasma and tissue and of molecular pathways activated by them. The results showed that treatment with irbesartan significantly increased EPC infiltration and decreased MP infiltration. The mechanisms underlying this response include the reduction/increase of a number of specific membrane receptors exposed by MPs (TF, P-Selectin, E-Selectin, PSGL-1, Rantes), respectively, by EPCs (β2-Integrins, α4β1-integrin), the augmentation of endothelium-mediated vasodilation and the reduction of protein expression of VEGF/SDF-1α followed by: (1) the diminishment of pro-inflammatory endothelial cytokines: VEGFR1, VEGFR2, CXCR4, Tie2, PIGF with role in EPC homing to sites of damaged endothelium; and (2) the increase of protein expression of COX-2, PGI2 synthase molecules with role in the improvement of arterial wall vasodilatation. In conclusion, the study underlines that irbesartan administration therapeutically improves/reduces EPC, respectively, MP mobilization and this action may be of salutary relevance contributing to its beneficial cardiovascular effects.