Molecular mechanisms of collagen isotype-specific modulation of smooth muscle cell phenotype.
Molecular mechanisms of collagen isotype-specific modulation of smooth muscle cell phenotype.
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DOI：
10.1161/atvbaha.108.178749
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Wamhoff BR
中科院分区：
文献类型：
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作者：
Orr AW;Lee MY;Lemmon JA;Yurdagul A Jr;Gomez MF;Bortz PD;Wamhoff BR
平滑肌细胞（SMC）表型调节是动脉粥样硬化进展的重要组成部分，受基质的严格调节，健康SMC基质的正常成分限制调节，动脉粥样硬化相关的过渡基质蛋白促进表型调节。我们试图确定IV型胶原（包括健康的动脉壁）和I型单体胶原（包括动脉粥样硬化病变）如何差异影响SMC表型。与I型胶原相比，IV型胶原上的SMC导致SMC收缩性蛋白的表达升高。与增强的收缩基因表达同时，胶原IV刺激SRF与平滑肌肌动蛋白和平滑肌肌球蛋白重链启动子中的CArG盒的结合。科尔IV还刺激了心肌素的表达，心肌素是驱动SMC特异性基因表达所需的关键SRF辅激活剂。与IV型胶原相反，I型胶原刺激炎症蛋白血管细胞粘附分子（VCAM）-1的表达增强。VCAM-1启动子中的NF-κB和NFAT结合位点对于I型胶原介导的VCAM-1启动子活性表达至关重要。然而，只有NFAT的抑制剂，而不是NF-κB，能够减少I型胶原相关的VCAM表达，并且I型胶原而不是IV型胶原刺激NFAT转录活性。这些结果首次表明，IV型胶原和I型胶原通过多种途径差异影响平滑肌表型调节。
Smooth muscle cell (SMC) phenotypic modulation, an important component of atherosclerosis progression, is critically regulated by the matrix, with normal components of the healthy SMC matrix limiting modulation and atherosclerosis-associated transitional matrix proteins promoting phenotypic modulation. We sought to determine how collagen IV (which comprises the healthy artery wall) and monomeric collagen I (which comprises atherosclerotic lesions) differentially affect SMC phenotype. Plating SMCs on collagen IV resulted in elevated expression of SMC contractility proteins compared to collagen I. Concurrent with enhanced contractile gene expression, collagen IV stimulates binding of SRF to CArG boxes in the promoters of smooth muscle actin and smooth muscle myosin heavy chain. Coll IV also stimulated the expression of myocardin, a critical SRF coactivator required to drive expression of SMC specific genes. In contrast to collagen IV, collagen I stimulated enhanced expression of the inflammatory protein vascular cell adhesion molecule (VCAM)-1. NF-κB and NFAT-binding sites in the VCAM-1 promoter are critical for collagen I–mediated expression of VCAM-1 promoter activity. However, only inhibitors of NFAT, not NF-κB, were able to reduce collagen I–associated VCAM expression, and collagen I but not collagen IV stimulated NFAT transcriptional activity. These results show for the first time that collagen IV and collagen I differentially affect smooth muscle phenotypic modulation through multiple pathways.