title: Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification.
abstract: Intimal calcification is highly correlated with atherosclerotic plaque burden, but the underlying mechanism is poorly understood. We recently reported that cartilage oligomeric matrix protein (COMP), a component of vascular extracellular matrix, is an endogenous inhibitor of vascular smooth muscle cell calcification.
  
  
  
  To investigate whether COMP affects atherosclerotic calcification.
  
  
  
  ApoE(-/-)COMP(-/-) mice fed with chow diet for 12 months manifested more extensive atherosclerotic calcification in the innominate arteries than did ApoE(-/-) mice. To investigate which origins of COMP contributed to atherosclerotic calcification, bone marrow transplantation was performed between ApoE(-/-) and ApoE(-/-)COMP(-/-) mice. Enhanced calcification was observed in mice transplanted with ApoE(-/-)COMP(-/-) bone marrow compared with mice transplanted with ApoE(-/-) bone marrow, indicating that bone marrow-derived COMP may play a critical role in atherosclerotic calcification. Furthermore, microarray profiling of wild-type and COMP(-/-) macrophages revealed that COMP-deficient macrophages exerted atherogenic and osteogenic characters. Integrin β3 protein was attenuated in COMP(-/-) macrophages, and overexpression of integrin β3 inhibited the shift of macrophage phenotypes by COMP deficiency. Furthermore, adeno-associated virus 2-integrin β3 infection attenuated atherosclerotic calcification in ApoE(-/-)COMP(-/-) mice. Mechanistically, COMP bound directly to β-tail domain of integrin β3 via its C-terminus, and blocking of the COMP-integrin β3 association by β-tail domain mimicked the COMP deficiency-induced shift in macrophage phenotypes. Similar to COMP deficiency in mice, transduction of adeno-associated virus 2-β-tail domain enhanced atherosclerotic calcification in ApoE(-/-) mice.
  
  
  
  These results reveal that COMP deficiency acted via integrin β3 to drive macrophages toward the atherogenic and osteogenic phenotype and thereby aggravate atherosclerotic calcification.
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Fu
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Cheng
authors.initials: C
authors.lastname: Gao
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Meili
authors.initials: M
authors.lastname: Wang
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Tuoyi
authors.initials: T
authors.lastname: Li
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Yiting
authors.initials: Y
authors.lastname: Jia
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Wanlin
authors.initials: W
authors.lastname: Zhu
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Cui
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Physiology and Pathophysiology (Y.F., C.G., Y.L., M.W., Y.H., T.L., Y.J., F.Y., X.W., W.K.), Department of Biomedical Informatics (W.M., Q.C.), Institute of Cardiovascular Sciences, School of Basic Medical Sciences (Y.L.), Peking University, Beijing, P. R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China (Y.F., C.G., Y.L., M.W., Y.H., W.M., T.L., Y.J., F.Y., Q.C., Y.L., X.W., W.K.); School of Biological Science and Medical Engineering, International Research Institute for Multidisciplinary Science, Beihang University, Beijing, P. R. China (W.Z.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.). kongw@bjmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064236:Cartilage Oligomeric Matrix Protein / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D064236:Cartilage Oligomeric Matrix Protein
keywords: atherosclerosis; cartilage oligomeric matrix protein; extracellular matrix; macrophages; phenotype; vascular calcification