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Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm.

ABSTRACT: Osteopontin (OPN) is associated with human abdominal aortic aneurysms (AAA) and in vitro studies suggest that this cytokine is downregulated by peroxisome proliferator-activated receptor (PPAR) ligation. We examined the effect of two PPAR ligands within a mouse model of aortic aneurysm.At 11 weeks of age apolipoprotein E deficient (ApoE(-/-)) mice were given pioglitazone (n=27), fenofibrate (n=27) or vehicle (n=27) in their drinking water. From 13 weeks of age mice received angiotensin II (1 microg/kg/min) infusion via subcutaneous pumps until death or 17 weeks when the aortas were harvested and maximum aortic diameters were recorded. Suprarenal aortic segments were assessed for OPN concentration and macrophage accumulation. Saline infused mice served as negative controls (n=22).Angiotensin II induced marked dilatation in the suprarenal aorta (>2-fold increase compared to controls) associated with upregulation of the cytokines OPN and macrophage infiltration. Suprarenal aortic expansion was significantly reduced by administration of pioglitazone (mean diameter 1.61+/-0.11 mm, p=0.011) and fenofibrate (mean diameter 1.51+/-0.13 mm, p=0.001) compared to the vehicle control group (mean diameter 2.10+/-0.14 mm). Immunostaining for macrophages was reduced in mice treated with pioglitazone (median staining area 6.2%, interquartile range 4.1-7.2, p<0.001) and fenofibrate (median staining area 4.0%, interquartile range 2.2-6.1, p<0.001) compared to mice receiving vehicle control (median staining area 13.2%, interquartile range 8.4-20.0).These findings suggest the potential value of peroxisome proliferator-activated receptor ligation as a therapy for human AAAs.

SUBMITTER: Golledge J

PROVIDER: S-EPMC2862103 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm.

Golledge Jonathan J Cullen Bradford B Rush Catherine C Moran Corey S CS Secomb Emma E Wood Frances F Daugherty Alan A Campbell Julie H JH Norman Paul E PE

Atherosclerosis 20091029 1

<h4>Objective</h4>Osteopontin (OPN) is associated with human abdominal aortic aneurysms (AAA) and in vitro studies suggest that this cytokine is downregulated by peroxisome proliferator-activated receptor (PPAR) ligation. We examined the effect of two PPAR ligands within a mouse model of aortic aneurysm.<h4>Methods</h4>At 11 weeks of age apolipoprotein E deficient (ApoE(-/-)) mice were given pioglitazone (n=27), fenofibrate (n=27) or vehicle (n=27) in their drinking water. From 13 weeks of age m ...[more]

PMID: 19926086

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm.

Publications

Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm.

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