Abstract 16543: The Atherosclerosis Candidate Gene Product Kalirin Reduces Atherosclerosis via Macrophage-Specific Mechanisms

Kalirin is a 270-kDa scaffolding protein comprising 2 GTP exchange factors (GEFs). KALRN has been associated with human atherosclerosis (athero) in multiple genetic studies, and carotid injury produced more neointimal hyperplasia in WT than in Kalrn-/+ mice. Therefore, we tested the hypothesis that Kalirin aggravates atherosclerosis (athero). Surprisingly, on Western diet Kalrn-/+/Apoe-/- mice developed 2.0±0.5-fold more aortic athero (en face, p<0.001) and 2.0±0.02-fold more brachiocephalic athero lesion area (p<0.005) than congenic Apoe-/- mice, even though blood pressures and serum cholesterols were equivalent. This anti-atherogenic activity of Kalirin resided, in part, in macrophages (Mϕs): LysM-Cre+/Kalrnflox/+/Apoe-/- mice evinced 1.3 ±0.2-fold more aortic athero than Kalrnflox/+/Apoe-/- mice (p<0.01). To test Kalirin effects on Mϕ activity, we used ≥3 independently isolated, matched Kalrn-/+ and WT bone marrow-derived Mϕ lines for each experiment. We tested RhoGEF activity by G-LISA: in response to...