Abstract 13431: Protease-Activated Receptor 4 Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm and Rupture
Objective: Platelets and the coagulation cascade are essential for hemostasis but also contribute to thrombosis. Levels of the coagulation protease thrombin are increased in patients with abdominal aortic aneurysms (AAAs). In mice, thrombin cleavage of protease-activated receptor 4 (PAR4) activates platelets. Angiotensin II (AngII) infusion into hypercholesterolemic mice induces formation of AAAs and can result in sudden death from rupture. At present, it is unknown if platelets and the coagulation cascade contribute to AAA formation. The purpose of this study was to determine the effects of PAR4 deficiency or platelet depletion in a mouse model of AngII-induced AAAs.
Methods and Results: Low-density lipoprotein receptor deficient (LDLr-/-) mice that were either PAR4+/+ (n = 12) or PAR4-/- (n = 17) were fed a fat-enriched diet (21% milk fat) and infused with AngII (1,000 ng/kg/min) for 28 days. Medial diameters of the suprarenal aortic region increased from 1.20 ± 0.07 mm in PAR4+/+ mice to 1.45 ± 0.10 mm in PAR4-/- mice (P = 0.036) as measured in vivo by ultrasound. PAR4 deficiency was also associated with 47% aortic rupture versus 0% in PAR4+/+ mice (P = 0.009). PAR4 deficiency had no effect on total plasma cholesterol concentrations, lipoprotein-cholesterol distributions, or the increased systolic blood pressure. Next, we determined the effects of platelet depletion on aortic rupture. AngII-infused mice were injected with an anti-CD42b antibody (glycoprotein 1bα, 5 µg/g body weight) every 3 days via tail vein injection (n = 5 each group). This group was compared to one administered an irrelevant IgG control. We observed 80% rupture in AngII-infused mice depleted of platelets versus 0% in the group administered irrelevant IgG (P = 0.048).
Conclusion: The presence of PAR4 is protective against the formation and rupture of AngII-induced AAAs. Rupture was also enhanced by platelet depletion. These results suggest that inhibition of platelet function may be detrimental in patients with AAAs.
- © 2011 by American Heart Association, Inc.