Hospital Clínico Universitario Virgen de la Arrixaca, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
Hospital Clínico Universitario Virgen de la Arrixaca, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
J Mol Cell Cardiol. 2015 May;82:218-27. doi: 10.1016/j.yjmcc.2015.03.015. Epub 2015 Mar 28.
Calumenin inhibits gamma-carboxylation of matrix-Gla-protein preventing BMP2-dependent calcification. Our aim was to explore the clinical relevance and functionality of the CALU polymorphism rs1043550, and the relationship of calumenin time-dependent expression profile with the active calcification of human vascular smooth muscle cells (hVSMC). Coronary artery calcium score and lesion severity were assessed by cardiac computed tomography in 139 consecutive low-risk patients genotyped for rs1043550. Polymorphic (G) allele carriage was associated with lower calcium (OR: 6.19, p=0.042). Calcified arteries from CALU 'A' allele carriers undergoing cardiovascular surgery exhibited higher residual calcification, higher calumenin immunostaining and lower matrix-Gla-protein, contrary to 'G' allele carriers. In a luciferase reporter system in vascular cells, polymorphic 'G' allele reduced the mRNA stability by 30% (p < 0.05). Osteogenic high-phosphate media induced active differentiation of hVSMC onto functional osteoblast-like cells as demonstrated by extracellular matrix mineralization and osteoblast markers expression. Calumenin was early over-expressed at day 3 (p < 0.05), but decreased thereafter (mRNA and protein) with implications on gamma-carboxylation system. Calumenin was found released and co-localizing with extracellular matrix calcifications. The CALU polymorphism rs1043550 affects mRNA stability and tissue availability of calumenin thus supporting the protective clinical significance. Calumenin shows a time-dependent profile during induced calcification. These data demonstrate a novel association of vascular calcification with the VSMC phenotypic transition into osteoblast-like cells. Moreover, hyperphosphatemic stimuli render calumenin accumulation in the mineralized extracellular matrix.
钙网蛋白抑制基质 Gla 蛋白的 γ-羧化，从而阻止 BMP2 依赖性钙化。我们的目的是探索 CALU 多态性 rs1043550 的临床相关性和功能，以及钙网蛋白时间依赖性表达谱与人类血管平滑肌细胞（hVSMC）活性钙化之间的关系。对 139 例连续低危患者进行了心脏 CT 冠状动脉钙评分和病变严重程度评估，并对 rs1043550 进行了基因分型。多态性（G）等位基因携带与较低的钙（OR：6.19，p=0.042）相关。接受心血管手术的钙网蛋白 'A' 等位基因携带者的钙化动脉表现出更高的残余钙化、更高的钙网蛋白免疫染色和更低的基质 Gla 蛋白，与 'G' 等位基因携带者相反。在血管细胞的荧光素酶报告基因系统中，多态性 'G' 等位基因使 mRNA 稳定性降低 30%（p < 0.05）。高磷成骨培养基诱导 hVSMC 向功能性成骨样细胞分化，表现为细胞外基质矿化和成骨细胞标志物表达。钙网蛋白在第 3 天（p < 0.05）早期过表达，但随后（mRNA 和蛋白质）减少，这对 γ-羧化系统有影响。钙网蛋白被释放并与细胞外基质钙化共定位。CALU 多态性 rs1043550 影响钙网蛋白的 mRNA 稳定性和组织可用性，从而支持其保护的临床意义。钙网蛋白在诱导钙化过程中呈现时间依赖性特征。这些数据表明，血管钙化与 VSMC 表型向成骨样细胞的转变之间存在新的关联。此外，高磷刺激使钙网蛋白在矿化的细胞外基质中积累。
