Abstract 444: Role of CaMKII in Atherosclerotic Plaque Progression in ApoE-Deficient Mice

Abstract

Non-obstructive mixed atherosclerotic plaques are an independent risk factor in predicting mortality in coronary artery disease patients. The multifactorial process of plaque progression and complication is a result of proliferation and migration of VSMCs and macrophages, apoptosis and calcification. A number of osteogenic regulators and inflammatory stimuli driving these processes in plaque advancement have been identified. Yet rupture, a result of complex mixed plaques, remains the leading cause of fatal cardiovascular events. Further understanding of the mechanisms underlying plaque progression is required to identify potential targets for therapies. Key signalling factors that modulate cell proliferation and migration, which potentially underlie plaque complication include the nodal multifunctional calcium/calmodulin dependent protein kinase II (CaMKII). Thus we hypothesized that, as plaques progress in a mouse model of atherosclerosis (ApoE -/- ), CaMKII activity would increase. We also hypothesized that systemic inhibition of CaMKII would impede plaque progression. Our data show a trend towards increased CaMKII phosphorylation, an indirect measure of kinase activity, in plaques as mice advance from 26 to 30 weeks. Pharmacological inhibition of CaMKII with KN-93, on alternate days for 4 weeks, in 30 week old mice reduced the incidence of calcification from 50% (KN-92 control: 4 out of 8) to 25% (KN-93: 2 out of 8). This was associated with a trend towards reduced calcification area (KN-92 control: 0.43mm 2 vs. KN-93: 0.06mm 2 ). These results suggest that CaMKII is activated during atherosclerosis and may be involved with plaque progression through calcification.