Abstract 21715: Transgenic Expression of S100a12 in Vascular Smooth Muscle Accelerates Atherosclerosis and Promotes Vascular Calcification
Background: S100A12 is a proinflammatory protein endogenously expressed in myeloid cells and is induced in vascular smooth muscle cells (VSMC) under pathological conditions such as coronary artery plaque rupture. We previously showed that C57BL6/J mice with VSMC targeted expression of S100A12 develop vascular degeneration and thoracic aortic aneurysms. We now tested the hypothesis that S100A12 augments atherosclerosis and possibly features of plaque instability.
Methods: S100A12 transgenic C57BL6/J mice were backcrossed 4 generations into ApoE null mice (S100A12-TG) and compared to wild type ApoE null littermate mice (WT). Mice (n=16 for each group) were kept on rodent chow and analyzed at age 4 and 11 months by in-vivo ultrasound, histology and gene expression studies in aortic tissue.
Results: At 11 month of age, S100A12-TG mice had larger aortic roots (2.1 ±0.2 vs. 1.6 ±0.2 mm, p<0.01) and larger atherosclerotic plaque size (1.4 fold in aortic arch and 1.5 fold in innominate artery, p<0.05). Atherosclerotic plaques in S100A12-TG mice had increased necrotic core area (34% vs. 8%, p<0.05) and increased elastic fiber break down (grade 3-4vs grade 2, p<0.05). Most strikingly, we observed large intravascular calcification in the S100A12-TG mice, which was nearly absent in the WT mice, and was also absent in age matched S100A12-TG ApoE+/+ mice. Intravascular calcification is preceded by increased gene expression of osteoblastic genes (BMP-5, DRP-1, BGLAP and others) in the aortic tissue of 4 month-old S100A12-TG mice, a time point by which vascular calcification was not yet present. Furthermore, aortic SMC isolated from S100A12-TG mice formed calcification nodules when cultured with conditioned media. This was dependent on NADPH oxidase since co-treatment with NADPH oxidase inhibitor apocynin or DPI prevented formation of calcified nodules in vitro.
Conclusions: Forced expression of human S100A12 in VSMC activates osteoblastic gene expression in the hyperlipedemic environment present in ApoE null mice, and is sufficient to promote plaque calcification and accelerates atherosclerosis with negative plaque remodeling. S100A12-ApoE null mice represent a novel in vivo model of accelerated atherosclerosis with features of plaque instability.
- © 2010 by American Heart Association, Inc.