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

ObjectivePeroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in the vasculature; however, the role of PPARγ in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPARγ in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPARγ-mediated signaling pathways that may prevent the development of AAA.MethodsWe determined whether periaortic application of CaCl2 renders vascular SMC-selective PPARγ knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.ResultsThere 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 mm [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 PPARγ signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPARγ overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPARγ 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 PPARγ 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-α expression.ConclusionIn this study, we identify PPARγ as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPARγ in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPARγ activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Clinical RelevanceAbdominal aortic aneurysm (AAA) is a common clinical disease and a leading cause of sudden death in cases of rupture. Many patients initially diagnosed with AAA are already at high risk for vessel wall rupture. Presently, there is no proven pharmacologic therapy for AAA in patients. The administration of pharmacologic agents may be a potentially promising strategy for reducing AAA development and rupture, particularly when the specified threshold diameter for surgical treatment of AAA has not yet been reached. Recent evidence in experimental models demonstrates that thiazolidinediones, clinically approved insulin-sensitizers that target peroxisome proliferator-activated receptor-γ (PPARγ), are effective at reducing AAA development; however, a role of PPARγ was not determined in those reports. Our present study extends those findings by describing the critical importance of vascular smooth muscle cell PPARγ in attenuating aortic dilatation and elastin degradation in the CaCl2-induced experimental aneurysm model. Our findings suggest that further elucidation of mechanisms resulting in PPARγ activation may represent a novel approach in the treatment of AAA in the clinical setting.