Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPARγ

Venkateswaran Subramanian, Jonathan Golledge, Talha Ijaz, Dennis Bruemmer, Alan Daugherty

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Rationale: Peroxisome proliferator-activated receptor (PPAR)γagonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPARγ, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs). Objective: To determine whether a PPARγ agonist reduces angiotensin II (Ang II)-induced atherosclerosis and AAAs via interaction with SMC-specific PPARγ. Methods and Results: Low-density lipoprotein receptor (LDLR)-/- mice with SMC-specific PPARγ deficiency were developed using PPARγfloxed (PPARγf/f) and SM22 Cremice. PPARγf/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 PPARγ 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 PPARγ 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 PPARγ 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 PPARγ deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre0/0 mice, but not in mice with SMC-specific PPARγ deficiency. SMC-specific PPARγ 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 PPARγ-deficient SMCs. Conclusions: Pio attenuates Ang II-induced atherosclerosis via the interaction with SMC-specific PPARγ, but has no effect on the development of AAAs.

Original languageEnglish
Pages (from-to)953-958
Number of pages6
JournalCirculation Research
Volume107
Issue number8
DOIs
StatePublished - Oct 15 2010

Keywords

  • Ang II
  • PPARγ
  • Pioglitazone
  • atherosclerosis
  • smooth muscle cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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