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


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.
Subramanian
Venkateswaran
V
Saha Cardiovascular Research Center, BBSRB, Room B243, University of Kentucky, Lexington, KY 40536-0509, USA.
Golledge
Jonathan
J
Ijaz
Talha
T
Bruemmer
Dennis
D
Daugherty
Alan
A
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D011973:Receptors, LDL; D045162:Thiazolidinediones; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000077205:Pioglitazone
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