Abstract 5194: Pioglitazone Attenuates Angiotensin II-induced Atherosclerosis via a Smooth Muscle Cell-Specific PPARgamma Mechanism but Has No Effect on Abdominal Aortic Aneurysms

Abstract

Objective: Chronic infusion of angiotensin II (AngII) augments development of atherosclerosis and induces abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Smooth muscle cells (SMCs) play a pivotal role in the development of these two pathologies. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have previously been shown to attenuate atherosclerosis in male mice. The purpose of the study was to determine the role of SMC-specific PPARgamma in ligand-mediated attenuation of AngII-induced atherosclerosis and AAAs. Methods and Results: Pairs of LDL receptor −/− mice with homozygous floxed PPARgamma alleles (PPARgammaf/f) were bred. Cre was expressed under the control of the SMC-specific promoter, SM22. Littermates were generated that did not express Cre (Cre0/0, n = 33) or were hemizygous for Cre (Cre1/0, n = 24). Male mice were fed a fat-enriched diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) with or without the PPARgamma agonist, pioglitazone (Pio - 20 mg/kg/day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. Pio administration attenuated AngII increased systolic blood pressure equivalently in both Cre0/0 and Cre1/0 groups. SMC-specific deficiency of PPARgamma or Pio administration had no effect on serum cholesterol concentrations and lipoprotein-cholesterol distributions. SMC-specific PPARgamma deficiency increased atherosclerosis (Cre1/0 = 11.6±1.5% versus Cre0/0 = 6.7±0.9% P<0.05). Pio administration reduced atherosclerosis in Cre0/0 mice (Pio-Cre0/0 = 2.9±0.4% versus Control-Cre0/0 = 6.7±0.9%, P<0.05, n=7–12 ), but failed to reduce atherosclerosis in mice with SMC-specific PPARgamma deficiency (Control-Cre1/0 = 11.6±1.5% versus Pio-Cre1/0 = 9.9±2.5%, P=NS). SMC-specific PPARgamma deficiency or Pio administration had no effect on AngII-induced AAAs as measured by ex vivo external diameter (Control-Cre0/0 = 2.0±0.2, Control-Cre1/0 = 2.4±0.4 versus Pio-Cre0/0 = 2.2±0.2, Pio-Cre1/0 = 1.9±0.2 mm, P=NS). Conclusion: Administration of Pio attenuates AngII-induced atherosclerosis via the activation of SMC-specific PPARgamma but did not influence formation of AAAs in male hypercholesterolemic mice. This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).