Clearance of Fetuin-A–Containing Calciprotein Particles Is Mediated by Scavenger Receptor-A

• Published in: Circulation research 2012-08, Vol.111 (5), p.575-584
• Main Authors: Herrmann, Marietta, Schäfer, Cora, Heiss, Alexander, Gräber, Steffen, Kinkeldey, Anne, Büscher, Andrea, Schmitt, Martin M.N, Bornemann, Jörg, Nimmerjahn, Falk, Herrmann, Martin, Helming, Laura, Gordon, Siamon, Jahnen-Dechent, Willi
• Format: Article
• Language: English
• Subjects: alpha-2-HS-Glycoprotein - genetics; alpha-2-HS-Glycoprotein - metabolism; alpha-2-HS-Glycoprotein - pharmacology; Animals; Apolipoproteins E - genetics; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Calcification, Physiologic - physiology; Calcinosis - metabolism; Calcinosis - pathology; Calcium - blood; Calcium-Binding Proteins - metabolism; Cardiology. Vascular system; Carotid Arteries - cytology; Cattle; Cell Line; Endocytosis - physiology; Fundamental and applied biological sciences. Psychology; Kupffer Cells - cytology; Kupffer Cells - metabolism; Lipoproteins, LDL - metabolism; Macrophages - cytology; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mononuclear Phagocyte System - metabolism; Phosphates - blood; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - metabolism; Spleen - cytology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.261479

RATIONALE:Fetuin-A is a liver-derived plasma protein involved in the regulation of calcified matrix metabolism. Biochemical studies showed that fetuin-A is essential for the formation of protein-mineral complexes, called calciprotein particles (CPPs). CPPs must be cleared from circulation to prevent local deposition and pathological calcification. OBJECTIVE:We studied CPP clearance in mice and in cell culture to identify the tissues, cells, and receptors involved in the clearance. METHODS AND RESULTS:In mice, fetuin-A–containing CPPs were rapidly cleared by the reticuloendothelial system, namely Kupffer cells of the liver and marginal zone macrophages of the spleen. Macrophages from scavenger receptor-AI/II (SR-A)-deficient mice cleared CPPs less efficiently than macrophages from wild-type mice, suggesting that SR-AI/II is involved in CPP binding and endocytosis. Accordingly, we found reduced clearance of CPPs in SR-A/MARCO–deficient mice. CONCLUSIONS:We could demonstrate that fetuin-A–containing CPPs facilitate the clearance of mineral debris by macrophages via SR-A. Since the same receptor also contributes to the uptake of modified low-density lipoprotein particles in atherosclerosis, defective endocytosis of both types of particle may impinge on lipid as well as mineral debris clearance in calcifying atherosclerosis.