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


METHODS
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).


RESULTS
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).


CONCLUSIONS
These findings suggest the potential value of peroxisome proliferator-activated receptor ligation as a therapy for human AAAs.
Golledge
Jonathan
J
The Vascular Biology Unit, School of Medicine, James Cook University, Townsville, QLD, Australia. jonathan.golledge@jcu.edu.au
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
D000804:Angiotensin II; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008024:Ligands; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D053495:Osteopontin / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation
D001057:Apolipoproteins E; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D053495:Osteopontin; D000804:Angiotensin II; D011345:Fenofibrate; D000077205:Pioglitazone