Abstract 13042: Ezrin Binding Phosphoprotein 50 Promotes Inflammation and Atherosclerosis
The PDZ-domain scaffolding protein, Ezrin Binding Phosphoprotein 50 (EBP50) is up-regulated following endoluminal injury and promotes neointima formation. However, the mechanisms underlying these effects are not fully understood. Because of the fundamental role that inflammation plays in vascular diseases we hypothesized that EBP50 mediates macrophage activation and the response of vessels to inflammation. EBP50 expression increased in primary macrophages and VSMC, and in the aorta of mice, upon treatment with LPS or TNFα. This increase was fully dependent on NF-kB activity. Conversely, activation of NF-kB was impaired in EBP50-null VSMC and macrophages. We found that inflammatory stimuli promote the formation of an EBP50-PKCzeta complex at the cell membrane that promotes IKK activation and NF-kB signaling. Macrophage activation and the expression of ICAM-1 and VCAM-1 in vascular cells after acute LPS treatment were reduced in EBP50-null cells and mice compared to WT. To determine the effect of EBP50 during vascular remodeling we performed wire injury in the femoral arteries of WT and EBP50-null mice. Macrophage recruitment to vascular lesions one week after injury was significantly reduced in EBP50 knockout mice. The effect of macrophage EBP50 on atherosclerosis was established in LDLR knockout mice. Mice were lethally irradiated and transplanted with bone marrow from either WT or EBP50-null mice and kept for 12 weeks on a high cholesterol diet. Full reconstitution of hematopoiesis by the donor marrow was established by “complete blood count” (CBC) and analysis of peritoneal macrophages for EBP50 expression. No differences in weight, blood glucose and cholesterol levels were observed between the two groups. Preliminary analysis by Oil Red-O staining of sections throughout the aorta showed a ~30% reduction in the area of atherosclerotic lesions in EBP50-null bone marrow recipients compared to WT. Collectively, these studies establish that EBP50 increases macrophage activation and the response of VSMC to inflammation. In conclusion, EBP50 is a key regulator of vascular remodeling under both acute and chronic inflammatory states.
- © 2013 by American Heart Association, Inc.