Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo
Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo
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DOI：
10.1161/atvbaha.110.206185
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发表时间：
2010-10-01
影响因子：
8.7
通讯作者：
Matsubara, Hiroaki
中科院分区：
文献类型：
--
作者：
Nakagawa, Yusuke;Ikeda, Koji;Matsubara, Hiroaki
血管钙化是心血管疾病的重要危险因素。在这里，我们研究了去分化的血管平滑肌细胞（VSMCs）在动脉粥样硬化内膜calcium.Methods和结果的作用，我们准备了人类培养的VSMCs在再分化或去分化状态和分析的基因表达的骨钙化调节因子。骨形态发生蛋白-2（BMP-2）是成骨细胞分化的有效起始物，其表达在去分化的VSMC中显著增强。此外，内源性BMP-2拮抗剂，如noggin，chordin，和基质γ-羧基谷氨酸蛋白，都在去分化的VSMCs下调。去分化的VSMCs的条件培养基，而不是从再分化的VSMCs，刺激间充质祖细胞C2 C12细胞，这是被取消的BMP-2敲除的成骨分化。在载脂蛋白（apo）E缺陷小鼠的动脉粥样硬化内膜中，α SM-肌动蛋白阳性细胞（推测为去分化的VSMCs）表达BMP-2。我们使用α SM-肌动蛋白启动子产生BMP-2转基因小鼠，并将它们与apoE缺陷小鼠（BMP-2转基因/apoE敲除）杂交。在BMP-2转基因/apoE基因敲除小鼠中检测到显著加速的动脉粥样硬化内膜钙化，尽管血清脂质浓度和动脉粥样硬化斑块大小与apoE基因敲除小鼠中的没有差异。增强的钙化似乎与成骨细胞样细胞在动脉粥样硬化内膜中的BMP-2转基因/apoE基因敲除mice. Conclusion，我们的研究结果共同证明了去分化的VSMC通过激活旁分泌BMP-2成骨信号在动脉粥样硬化钙化的病理生理学中的重要作用。（Arterioscler Thromb Vasc Biol.2010;30：1908-1915.）
Objective-Vascular calcification is an important risk factor for cardiovascular diseases. Here, we investigated a role of dedifferentiated vascular smooth muscle cells (VSMCs) in the atherosclerotic intimal calcification.Methods and Results-We prepared human cultured VSMCs in either redifferentiatiated or dedifferentiated state and analyzed the gene expressions of bone-calcification regulatory factors. Expression of bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblast differentiation, was significantly enhanced in dedifferentiated VSMCs. Furthermore, endogenous BMP-2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein, were all downregulated in the dedifferentiated VSMCs. Conditioned medium from dedifferentiated VSMCs, but not from redifferentiated VSMCs, stimulated the osteoblastic differentiation of the mesenchymal progenitor C2C12 cells, which was abolished by BMP-2 knockdown. In atherosclerotic intima from apolipoprotein (apo) E-deficient mice, alpha SM-actin-positive cells, presumably dedifferentiated VSMCs, expressed BMP-2. We generated BMP-2-transgenic mice using alpha SM-actin promoter and crossed them with apoE-deficient mice (BMP-2-transgenic/apoE-knockout). Significantly accelerated atherosclerotic intimal calcification was detected in BMP-2-transgenic/apoE-knockout mice, although serum lipid concentration and atherosclerotic plaque size were not different from those in apoE-knockout mice. Enhanced calcification appeared to be associated with the frequent emergence of osteoblast-like cells in atherosclerotic intima in BMP-2-transgenic/apoE-knockout mice.Conclusion-Our findings collectively demonstrate an important role of dedifferentiated VSMCs in the pathophysiology of atherosclerotic calcification through activating paracrine BMP-2 osteogenic signals. (Arterioscler Thromb Vasc Biol. 2010;30:1908-1915.)