Gla-Rich Protein Acts as a Calcification Inhibitor in the Human Cardiovascular System
| Autor: | Marta S. Rafael, Brecht A. G. Willems, José L. Enriquez, José Neves, Inês M. Luís, Sofia Cavaco, Anjos L. Macedo, Ruben Martins Da Costa, Cees Vermeer, Dina C. Simes, Rui Vitorino, Carla Viegas, Sofia Duque Santos, Alexandra Teixeira |
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| Přispěvatelé: | Promovendi CD, Biochemie, RS: CARIM - R1 - Thrombosis and haemostasis |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male medicine.medical_specialty Vascular smooth muscle Calcification inhibitor alpha-2-HS-Glycoprotein Osteocalcin Coronary Artery Disease Extracellular matrix Tissue Culture Techniques Internal medicine Calcium-binding protein Matrix gla protein medicine aortic valve calcification of Humans Osteopontin Aorta Aged Aged 80 and over Extracellular Matrix Proteins biology Calcium-Binding Proteins calcification of Intracellular Signaling Peptides and Proteins Calcinosis Proteins Aortic Valve Stenosis Middle Aged medicine.disease Coronary Vessels aortic valve multivesicular bodies Actins Endocrinology Gene Expression Regulation vascular calcification Case-Control Studies biology.protein gene expression Intercellular Signaling Peptides and Proteins Calcium Female Cardiology and Cardiovascular Medicine hormones hormone substitutes and hormone antagonists Calcification |
| Zdroj: | Arteriosclerosis Thrombosis and Vascular Biology, 35(2), 399-408. LIPPINCOTT WILLIAMS & WILKINS |
| ISSN: | 1079-5642 |
| DOI: | 10.1161/atvbaha.114.304823 |
| Popis: | Objective— Vascular and valvular calcifications are pathological processes regulated by resident cells, and depending on a complex interplay between calcification promoters and inhibitors, resembling skeletal metabolism. Here, we study the role of the vitamin K–dependent Gla-rich protein (GRP) in vascular and valvular calcification processes. Approach and Results— Immunohistochemistry and quantitative polymerase chain reaction showed that GRP expression and accumulation are upregulated with calcification simultaneously with osteocalcin and matrix Gla protein (MGP). Using conformation-specific antibodies, both γ-carboxylated GRP and undercarboxylated GRP species were found accumulated at the sites of mineral deposits, whereas undercarboxylated GRP was predominant in calcified aortic valve disease valvular interstitial cells. Mineral-bound GRP, MGP, and fetuin-A were identified by mass spectrometry. Using an ex vivo model of vascular calcification, γ-carboxylated GRP but not undercarboxylated GRP was shown to inhibit calcification and osteochondrogenic differentiation through α-smooth muscle actin upregulation and osteopontin downregulation. Immunoprecipitation assays showed that GRP is part of an MGP–fetuin-A complex at the sites of valvular calcification. Moreover, extracellular vesicles released from normal vascular smooth muscle cells are loaded with GRP, MGP, and fetuin-A, whereas under calcifying conditions, released extracellular vesicles show increased calcium loading and GRP and MGP depletion. Conclusions— GRP is an inhibitor of vascular and valvular calcification involved in calcium homeostasis. Its function might be associated with prevention of calcium-induced signaling pathways and direct mineral binding to inhibit crystal formation/maturation. Our data show that GRP is a new player in mineralization competence of extracellular vesicles possibly associated with the fetuin-A–MGP calcification inhibitory system. GRP activity was found to be dependent on its γ-carboxylation status, with potential clinical relevance. |
| Databáze: | OpenAIRE |
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