Subramanian, Venkateswaran, Bruemmer, Dennis, Golledge, Jonathan, and Daugherty, Alan (2009) Pioglitazone attenuates angiotensin II-induced atherosclerosis via a smooth muscle cell-specific ppargamma mechanism but has no effect on abdominal aortic aneurysms. In: Circulation (120) 5194. S1066-S1067. From: American Heart Association Meeting, 14-18 November 2009, Orlando, FL, USA.

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Abstract

Objective: Chronic infusion of angiotensin II (AngII) augments development of atherosclerosis and induces abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Smooth muscle cells (SMCs) play a pivotal role in the development of these two pathologies. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have previously been shown to attenuate atherosclerosis in male mice. The purpose of the study was to determine the role of SMC-specific PPARgamma in ligand-mediated attenuation of AngII-induced atherosclerosis and AAAs.

Methods and Results: Pairs of LDL receptor –/– mice with homozygous floxed PPARgamma alleles (PPARgammaf/f) were bred. Cre was expressed under the control of the SMC-specific promoter, SM22. Littermates were generated that did not express Cre (Cre0/0, n = 33) or were hemizygous for Cre (Cre1/0, n = 24). Male mice were fed a fat-enriched diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) with or without the PPARgamma agonist, pioglitazone (Pio - 20 mg/kg/day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. Pio administration attenuated AngII increased systolic blood pressure equivalently in both Cre0/0 and Cre1/0 groups. SMC-specific deficiency of PPARgamma or Pio administration had no effect on serum cholesterol concentrations and lipoprotein-cholesterol distributions. SMC-specific PPARgamma deficiency increased atherosclerosis (Cre1/0 = 11.6±1.5% versus Cre0/0 = 6.7±0.9% P<0.05). Pio administration reduced atherosclerosis in Cre0/0 mice (Pio-Cre0/0 = 2.9±0.4% versus Control-Cre0/0 = 6.7±0.9%, P<0.05, n=7–12 ), but failed to reduce atherosclerosis in mice with SMC-specific PPARgamma deficiency (Control-Cre1/0 = 11.6±1.5% versus Pio-Cre1/0 = 9.9±2.5%, P=NS). SMC-specific PPARgamma deficiency or Pio administration had no effect on AngII-induced AAAs as measured by ex vivo external diameter (Control-Cre0/0 = 2.0±0.2, Control-Cre1/0 = 2.4±0.4 versus Pio-Cre0/0 = 2.2±0.2, Pio-Cre1/0 = 1.9±0.2 mm, P=NS).

Conclusion: Administration of Pio attenuates AngII-induced atherosclerosis via the activation of SMC-specific PPARgamma but did not influence formation of AAAs in male hypercholesterolemic mice.

Item ID:	25042
Item Type:	Conference Item (Abstract / Summary)
ISSN:	1524-4539
Related URLs:	Publisher
Additional Information:	Circulation (2009), Volume 120, Issue 18 Supplement
Date Deposited:	20 Feb 2013 09:20
FoR Codes:	11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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