Abstract 378: Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E-deficient mice

Abstract

Atherothrombosis is the cause of death of over 14 million people per year worldwide and murine models to replicate this process in vivo are mostly lacking. Previously we demonstrated that silencing of anticoagulant protein C using RNA interference ( siProc ) induces spontaneous atherothrombosis in the aortic root of apolipoprotein E-deficient ( Apoe -/- ) mice, albeit at a low incidence rate. Here we aim to determine if plaque susceptibility for rupture can be linked to plaque characteristics and/or blood composition, and moreover, we attempt to boost incidence through a transient increase in blood pressure as well as to localize atherothrombosis to an additional predefined vascular site by means of a semi-constrictive collar around the carotid artery. In the current study, si Proc -driven spontaneous atherothrombosis in the aortic root of Apoe-/- mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe -/- mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, and serum amyloid A were not different amongst si Proc -treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe -/- mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.