Pioglitazone-Induced Reductions in Atherosclerosis Occur via Smooth Muscle Cell-Specific Interaction With PPARγ

Rationale: Peroxisome proliferator-activated receptor (PPAR)gamma agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPAR gamma, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs). Objective: To determine whether a PPAR gamma agonist reduces angiotensin II (Ang II)-induced atherosclerosis and AAAs via interaction with SMC-specific PPAR gamma. Methods and Results: Low-density lipoprotein receptor (LDLR)(-/-) mice with SMC-specific PPAR gamma deficiency were developed using PPAR gamma floxed (PPAR gamma(f/f)) and SM22 Cre(+) mice. PPAR gamma(f/f) littermates were generated that did not express Cre (Cre(0/0)) or were hemizygous for Cre (Cre(+/0)). To assess the contribution of SMC-specific PPAR gamma in ligand-mediated attenuation of Ang II-induced atherosclerosis and AAAs, both male and female Cre(0/0) and Cre(+/0) mice were fed a fat-enriched diet with or without the PPAR gamma agonist pioglitazone (Pio) (20 mg/kg per day) for 5 weeks. After 1 week of feeding modified diets, mice were infused with Ang II (1000 ng/kg per minute) for 4 weeks. SMC-specific PPAR gamma deficiency or Pio administration had no effect on plasma cholesterol concentrations. Pio administration attenuated Ang II-increased systolic blood pressure equivalently in both Cre(0/0) and Cre(+/0) groups. SMC-specific PPAR gamma deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre(0/0) mice, but not in mice with SMC-specific PPAR gamma deficiency. SMC-specific PPAR gamma deficiency or Pio administration had no effect on Ang II-induced AAA development. Pio also did not attenuate Ang II-induced monocyte chemoattractant protein-1 production in PPAR gamma-deficient SMCs. Conclusions: Pio attenuates Ang II-induced atherosclerosis via the interaction with SMC-specific PPAR gamma, but has no effect on the development of AAAs. (Circ Res. 2010;107:953-958.)