Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan.
J Biol Chem. 2012 Aug 31;287(36):30336-45. doi: 10.1074/jbc.M111.329110. Epub 2012 Jul 9.
Differentiation of vascular smooth muscle cells (SMCs) into osteoblast-like cells is considered to be a mechanism of vascular calcification. However, regulators of osteoblast-like differentiation of vascular SMCs are not fully elucidated. Here, we investigated the expression of bone morphogenetic protein (BMP)-binding endothelial cell precursor-derived regulator (BMPER), a vertebrate homologue of Drosophila crossveinless-2, in vascular SMCs and the role and mode of action of BMPER in osteoblast-like differentiation of human coronary artery SMCs (HCASMCs). BMPER was expressed in cultured human vascular SMCs, including HCASMCs. Silencing of endogenous BMPER expression by an RNA interference technique inhibited osteoblast-like differentiation of HCASMCs, as evaluated by up-regulation of osteoblast markers such as alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2), by down-regulation of a SMC marker α-smooth muscle actin (αSMA), and by mineralization. Treatment with recombinant BMPER enhanced, whereas BMP-2 reduced osteoblast-like differentiation. BMPER antagonized BMP-2-induced phosphorylation of Smad 1/5/8, suggesting that the effect of BMPER was mediated by antagonizing the action of BMP. BMPER increased IκBα phosphorylation and NF-κB activity and specific NF-κB decoy oligonucleotides deteriorated osteoblast-like differentiation of HCASMCs by BMPER. In human coronary artery with atherosclerotic plaque containing calcification, the BMPER-positive signals were observed in the neointimal and medial SMCs in the vicinity of the plaque. These findings indicate that BMPER is a novel regulator of the osteoblast-like differentiation of HCASMCs.
血管平滑肌细胞 (SMCs) 向成骨样细胞的分化被认为是血管钙化的一种机制。然而，血管 SMC 向成骨样分化的调节因子尚未完全阐明。在这里，我们研究了骨形态发生蛋白 (BMP) 结合内皮细胞前体细胞衍生的调节剂 (BMPER) 在血管 SMC 中的表达，BMPER 是果蝇无横脉 2 的脊椎动物同源物，以及 BMPER 在人冠状动脉平滑肌细胞 (HCASMC) 中成骨样分化中的作用和作用模式。BMPER 在培养的人血管 SMC 中表达，包括 HCASMC。通过 RNA 干扰技术沉默内源性 BMPER 表达抑制了 HCASMC 的成骨样分化，通过上调成骨标志物如碱性磷酸酶 (ALP) 和 runt 相关转录因子 2 (Runx2)、下调平滑肌标志物 α-平滑肌肌动蛋白 (αSMA) 和矿化来评估。重组 BMPER 增强了成骨样分化，而 BMP-2 则降低了成骨样分化。BMPER 拮抗 BMP-2 诱导的 Smad 1/5/8 磷酸化，表明 BMPER 的作用是通过拮抗 BMP 的作用来介导的。BMPER 增加了 IκBα 磷酸化和 NF-κB 活性，并且特定的 NF-κB 诱饵寡核苷酸通过 BMPER 恶化了 HCASMC 的成骨样分化。在含有钙化斑块的人冠状动脉中，在斑块附近的内膜和中膜 SMC 中观察到 BMPER 阳性信号。这些发现表明 BMPER 是 HCASMC 成骨样分化的一种新的调节因子。
