Interaction between Angiotensin II, Osteoprotegerin, and Peroxisome Proliferator-Activated Receptor-γ in Abdominal Aortic Aneurysm

Abstract

Background and Aims: Osteoprotegerin (OPG) has been associated with abdominal aortic aneurysm (AAA) expansion. Angiotensin II (AngII) receptor blockade has been shown to reduce OPG expression in human AAA tissue. Interaction between vascular AngII and OPG was further examined using cell culture and the AngII-infused ApoE^–/– mouse AAA model. The ability of peroxisome proliferator-activated receptor-γ (PPARγ) activation to target OPG as potential therapy for AAA was also investigated. Methods and Results: Human aortic smooth muscle cells (AoSMC) exposed to AngII exhibited dose-dependent increase in the production OPG. A 3-fold increase in suprarenal aortic concentration of OPG was observed in AngII-infused ApoE^–/– mice. AngII type 1 receptor expression in human AAA tissue, and AoSMC in vitro, was stimulated up 4-fold in the presence of OPG. This effect in AoSMC was counteracted in the presence of the PPARγ ligand, pioglitazone. Addition of PPARγ ligand to cultured human AAA explant reduced OPG secretion by 60% and tissue concentration of OPG and metalloproteinase 9 by 2- and 3-fold, respectively. Administration of pioglitazone to AngII-infused ApoE^–/– mice significantly reduced aortic concentrations of OPG and metalloproteinase 9. Conclusions: These data support an interaction between AngII and OPG in aneurysm formation. Activation of PPARγ may have a role in treatment of AAA.