Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPAR{gamma}.

نویسندگان

  • Venkateswaran Subramanian
  • Jonathan Golledge
  • Talha Ijaz
  • Dennis Bruemmer
  • Alan Daugherty
چکیده

RATIONALE Peroxisome proliferator-activated receptor (PPAR)γ agonists 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 PPARγ floxed (PPARγ(f/f)) and SM22 Cre(+) mice. PPARγ(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 PPARγ 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 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 Cre(0/0) and Cre(+/0) groups. SMC-specific PPARγ deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre(0/0) 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.

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Molecular Medicine Short Communication Pioglitazone-Induced Reductions in Atherosclerosis Occur via Smooth Muscle Cell–Specific Interaction With PPAR

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عنوان ژورنال:
  • Circulation research

دوره 107 8  شماره 

صفحات  -

تاریخ انتشار 2010