Interaction between Angiotensin II, Osteoprotegerin, and Peroxisome Proliferator-Activated Receptor-<symbol unicode="03B3" ascii="gamma"></symbol> in Abdominal Aortic Aneurysm

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(PPAR ) 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 3fold 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 PPAR ligand, pioglitazone. Addition of PPAR ligand to cultured human AAA explant reduced OPG secretion by 60% and tissue concentration of OPG and metalloproteinase 9 by 2and 3fold, respectively. Administration of pioglitazone to AngIIReceived: October 10, 2007 Accepted after revision: May 1, 2008 Published online: October 16, 2008 Prof. Jonathan Golledge Vascular Biology Unit, Department of Surgery School of Medicine, James Cook University Townsville, Qld. 4811 (Australia) Tel. +61 7 4796 1417, Fax +61 7 4796 1401, E-Mail [email protected] © 2008 S. Karger AG, Basel Accessible online at: www.karger.com/jvr D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /1 8/ 20 17 7 :3 8: 24 A M Moran /Cullen /Campbell /Golledge J Vasc Res 2009;46:209–217 210 by activation of the nuclear receptor, peroxisome proliferator-activated receptor (PPAR ) [5] . PPAR has been identified as the target receptor of the thiazolidinedione group of insulin sensitizing drugs now widely used for treating type 2 diabetes [4] . In addition to influencing VSMC expression of OPG, thiazolidinediones have been shown to downregulate expression of other cytokines and proteolytic enzymes, suggesting a potential role of this medication in inhibiting progression of AAA [7] . In the present study, we investigated the link between AngII and OPG in vitro and in vivo, and hypothesized that thiazolidinediones, by downregulating OPG within AoSMC in addition to anti-inflammatory pathways, would reduce pathology associated with aortic wall degeneration and AAA expansion.