Loss of Id3 Increases VCAM-1 Expression, Macrophage Accumulation, and Atherogenesis in Ldlr−/− Mice

Abstract
Objective—Inhibitor of differention-3 (Id3) promotes B cells homing to the aorta and atheroprotection in Apoe−/− mice. We sought to determine the impact of loss of Id3 in the Ldlr−/− mouse model of diet-induced atherosclerosis and identify novel Id3 targets in the vessel wall.
Methods and Results—Ex vivo optical imaging confirmed that Id3−/− Ldlr−/− mice have significantly fewer aortic B cells than Id3+/+ Ldlr−/− mice. After 8 and 16 weeks of Western diet, Id3−/− Ldlr−/− mice developed significantly more atherosclerosis than Id3+/+ Ldlr−/− mice, with Id3+/− Ldlr−/− mice demonstrating an intermediate phenotype. There were no differences in serum lipid levels between genotypes. Immunostaining demonstrated that aortas from Id3−/− Ldlr−/− mice had greater intimal macrophage density and CCL 20 and vascular cell adhesion molecule 1 (VCAM-1) expression compared with Id3+/+ Ldlr−/− mice. Real-time polymerase chain reaction demonstrated increased VCAM-1 mRNA levels in the aortas of Id3−/− Ldlr−/− mice. Primary vascular smooth muscle cells from Id3−/− mice expressed greater amounts of VCAM-1 protein compared with control. Gain and loss of function studies in primary vascular smooth muscle cells identified a role for Id3 in repressing VCAM-1 promoter activation. Chromatin immunoprecipitation demonstrated interaction of E12 with the VCAM-1 promoter, which is inhibited by Id3.
Conclusion—Id3 is an atheroprotective transcription regulator with targets in both B cells and vessel wall cells leading to reduced macrophages accumulation and reduced atherosclerosis formation.
- Received March 30, 2012.
- Accepted September 7, 2012.
- © 2012 American Heart Association, Inc.
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- Loss of Id3 Increases VCAM-1 Expression, Macrophage Accumulation, and Atherogenesis in Ldlr−/− MiceMichael J. Lipinski, Kirsti A. Campbell, Son Q. Duong, Thomas J. Welch, James C. Garmey, Amanda C. Doran, Marcus D. Skaflen, Stephanie N. Oldham, Kimberly A. Kelly and Coleen A. McNamaraArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300352, originally published October 4, 2012https://doi.org/10.1161/ATVBAHA.112.300352
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- Loss of Id3 Increases VCAM-1 Expression, Macrophage Accumulation, and Atherogenesis in Ldlr−/− MiceMichael J. Lipinski, Kirsti A. Campbell, Son Q. Duong, Thomas J. Welch, James C. Garmey, Amanda C. Doran, Marcus D. Skaflen, Stephanie N. Oldham, Kimberly A. Kelly and Coleen A. McNamaraArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300352, originally published October 4, 2012https://doi.org/10.1161/ATVBAHA.112.300352