Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ deletion promotes abdominal aortic aneurysms

Objective: Peroxisome proliferator-activated receptor-gamma (PPAR gamma) plays an important role in the vasculature; however, the role of PPAR gamma in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR gamma in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR gamma-mediated signaling pathways that may prevent the development of AAA. Methods: We determined whether periaortic application of CaCl2, renders vascular SMC-selective PPAR gamma knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture. Results: There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl2 application in SMPG KO mice compared with littermate controls (1.4 +/- 0.3 [n = 8] vs 1.1 +/- 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl2 to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR gamma signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR gamma overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR gamma bound to a peroxisome proliferator-activated receptor response element (PPRE) 141 to 159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR gamma overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-alpha expression. Conclusion: In this study, we identify PPAR gamma as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR gamma in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR gamma activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture. (J Vase Surg 2010;52:984-93.)