Modulation of cysteine-rich protein 2 expression in vascular injury and atherosclerosis
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Vascular smooth muscle cells (VSMCs) of the arterial wall normally display a differentiated and contractile phenotype. In response to arterial injury, VSMCs switch to a synthetic phenotype, contributing to vascular remodeling. Cysteine-rich protein 2 (CRP2) is a cytoskeletal protein expressed in VSMCs and blunts VSMC migration in part by sequestering the scaffolding protein p130Cas at focal adhesions. CRP2 deficiency in mice increases neointima formation following arterial injury. The goal of this study was to use Csrp2 promoter-lacZ transgenic mice to analyze CRP2 expression during VSMC phenotypic modulation. In a neointima formation model after carotid artery cessation of blood flow, lacZ reporter activity and smooth muscle (SM) α-actin expression in the media were rapidly downregulated 4 days after carotid ligation. Fourteen days after ligation, there was a high level expression of both Csrp2 promoter activity and SM α-actin protein expression in neointimal cells. In atherosclerosis prone mice fed an atherogenic diet, Csrp2 promoter activity was detected within complex atherosclerotic lesions. Interestingly, Csrp2 promoter activity was also present in the fibrous caps of complicated atherosclerotic lesions, indicating that CRP2 might contribute to plaque stability. These findings support the concept that CRP2 contributes to the phenotypic modulation of VSMCs during vascular disease. Modulating transcription to increase CRP2 expression during vascular injury might attenuate vascular remodeling. In addition, increased CRP2 expression at the fibrous caps of advanced lesions might also serve to protect atherosclerotic plaques from rupture.
KeywordsCysteine-rich protein 2 Vascular smooth muscle cells Transgenic mice Vascular injury Atherosclerosis
This work was supported by grants from the National Science Council, Taiwan (101-2320-B-400-002-MY3 to S.-F.Y.), National Health Research Institutes (CS-103-PP-05 to S.-F.Y.), and the National Institutes of Health (HL-078869 to M.D.L.). This research was conducted under the Graduate Program of Biotechnology in Medicine sponsored by the National Tsing Hua University and the National Health Research Institutes. We thank the Pathology Core Laboratory of the National Health Research Institutes for processing and embedding of tissue samples. We thank Wun-Chu Fan for assistance in histological analysis.
- 4.Jain MK, Fujita KP, Hsieh CM, Endege WO, Sibinga NE, Yet SF, Kashiki S, Lee WS, Perrella MA, Haber E, Lee ME (1996) Molecular cloning and characterization of SmLIM, a developmentally regulated LIM protein preferentially expressed in aortic smooth muscle cells. J Biol Chem 271(17):10194–10199PubMedCrossRefGoogle Scholar
- 5.Yet SF, Folta SC, Jain MK, Hsieh CM, Maemura K, Layne MD, Zhang D, Marria PB, Yoshizumi M, Chin MT, Perrella MA, Lee ME (1998) Molecular cloning, characterization, and promoter analysis of the mouse Crp2/SmLim gene: preferential expression of its promoter in the vascular smooth muscle cells of transgenic mice. J Biol Chem 273(17):10530–10537PubMedCrossRefGoogle Scholar
- 11.Perrella MA, Pellacani A, Layne MD, Patel A, Zhao D, Schreiber BM, Storch J, Feinberg MW, Hsieh CM, Haber E, Lee ME (2001) Absence of adipocyte fatty acid binding protein prevents the development of accelerated atherosclerosis in hypercholesterolemic mice. FASEB J 15(10):1774–1776PubMedGoogle Scholar