CALU polymorphism A29809G affects calumenin availability involving vascular calcification. (May 2015)

• Record Type: Journal Article
• Authors: Jover, Eva; Marín, Francisco; Quintana, Míriam; Pérez-Andreu, Joaquín; Hurtado, José Antonio; Rodríguez, Cristina; Martínez-González, José; González-Conejero, Rocío; Valdés, Mariano; Hernández-Romero, Diana
• Is Part Of: Journal of molecular and cellular cardiology. Volume 82(2015:May)
• Page Start: 218
• Page End: 227
• Publication Date: 2015-05
• Subjects: Calumenin -- Vascular calcification -- Gamma-carboxylation -- Vascular smooth muscle cell -- rs1043550; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.03.015
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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. Highlights: 3′UTR CALU SNP rs1043550 is protective for coronary calcification compared to wild-type. 3′UTR CALU SNP rs1043550 renders low expression of calumenin. Calumenin expression is time-dependent in VSMC under hyperphosphatemia. Hyperphosphatemia promotes calumenin secretion into mineralized ECM. Gamma-carboxylation is restored at late stages of VSMC under hyperphosphatemia.