Pioglitazone-induced reductions in Atherosclerosis occur via smooth muscle cell–Specific interaction with PPARƴ

Abstract

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 (Cre0/0) 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 Cre0/0 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 Cre0/0 and Cre+/0 groups. SMC-specific PPAR{gamma} deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre0/0 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.