PPARδ reduces abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice by regulating extracellular matrix homeostasis and inflammatory responses

Background: Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by a localized degradation of connective tissue and apoptosis of vascular smooth muscle cells. This study examined whether the ligand-activated peroxisome proliferator-activated receptor (PPAR) delta can directly antagonize angiotensin II (Ang II)-induced AAA formation in apoE-deficient mice. Methods and results: Six-month-old male apoE-deficient mice were infused with Ang II and/or GW501516 (1.44 and 3.3 mg/kg/day, respectively) via osmotic mini-pumps. At day 28, aortic size was measured and tissues were collected for analyses. Co-infusion of GW501516, an activator of PPARd, attenuated both the incidence and the severity of Ang II-induced AAA in apoE-deficient mice. Ligand-activated PPARd also reduced infiltration of macrophages, resulting in significant decreases in chemotactic proteins such as monocyte chemoattractant protein-1, macrophage inflammatory protein-1 beta, and inducible nitric oxide synthase. The anti-inflammatory effect of GW501516 was associated with the suppression of apoptotic cell death, along with the inhibition of medial smooth muscle cell loss and focal elastin destruction, which leads to a medial dissection and aortic rupture. These ameliorative effects of GW501516 on Ang II-induced aneurysm were correlated with increased expression of extracellular matrix (ECM) proteins, such as types I and III collagen, fibronectin, and elastin, along with the up-regulation of transforming growth factor-beta 1. In addition, ligand-activated PPAR delta also increased the expression of tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3, while it strongly suppressed that of matrix metalloproteinase-2. Conclusions: PPARd attenuates Ang II-induced AAA formation by regulating ECM homeostasis and inflammatory responses, suggesting a novel strategy for the treatment of AAA. (c) 2014 Elsevier Ireland Ltd. All rights reserved.