title: Local Production of Fatty Acid-Binding Protein 4 in Epicardial/Perivascular Fat and Macrophages Is Linked to Coronary Atherosclerosis.
abstract: Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and elevated circulating FABP4 level is associated with obesity-mediated metabolic phenotype. We systematically investigated roles of FABP4 in the development of coronary artery atherosclerosis.
  
  
  
  First, by immunohistochemical analyses, we found that FABP4 was expressed in macrophages within coronary atherosclerotic plaques and epicardial/perivascular fat in autopsy cases and macrophages within thrombi covering ruptured coronary plaques in thrombectomy samples from patients with acute myocardial infarction. Second, we confirmed that FABP4 was secreted from macrophages and adipocytes cultured in vitro. Third, we investigated the effect of exogenous FABP4 on macrophages and human coronary artery-derived smooth muscle cells and endothelial cells in vitro. Treatment of the cells with recombinant FABP4 significantly increased gene expression of inflammatory markers in a dose-dependent manner. Finally, we measured serum FABP4 level in the aortic root (Ao-FABP4) and coronary sinus (CS-FABP4) of 34 patients with suspected or known coronary artery disease. Coronary stenosis score assessed by the modified Gensini score was weakly correlated with CS-FABP4 but was not correlated with Ao-FABP4. A stronger correlation (r=0.59, P<0.01) was observed for the relationship between coronary stenosis score and coronary veno-arterial difference in FABP4 level, (CS-Ao)-FABP4, indicating local production of FABP4 during coronary circulation in the heart. Multivariate analysis indicated that (CS-Ao)-FABP4 was an independent predictor of the severity of coronary stenosis after adjustment of conventional risk factors.
  
  
  
  FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis.
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.). furuhasi@sapmed.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Furuhashi
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fuseya
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Masaki
authors.initials: M
authors.lastname: Murata
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hoshina
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Shutaro
authors.initials: S
authors.lastname: Ishimura
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Mita
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Akina
authors.initials: A
authors.lastname: Omori
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Megumi
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishida
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kokubu
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Marenao
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Norihito
authors.initials: N
authors.lastname: Moniwa
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Norimasa
authors.initials: N
authors.lastname: Sawada
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
authors.affiliation: From the Departments of Cardiovascular, Renal, and Metabolic Medicine (M.F., T.F., K.H., S.I., T.M., Y.W., A.O., M.M., J.N., N.K., M.T., N.M., H.Y., T.M.) and Molecular and Cellular Pathology (M.M., N.S.), Sapporo Medical University School of Medicine, Sapporo, Japan; Sapporo Medical University, Chuo-ku, Sapporo, Japan (K.S.); Department of Cardiovascular Internal Medicine, Obihiro Kosei Hospital, Obihiro, Japan (S.I., T.M.); Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan (T.S.); and CIMIC Co, Ltd, Yushima, Bunkyo-ku, Tokyo, Japan (T.S., T.O.).
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D023921:Coronary Stenosis / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D015999:Multivariate Analysis; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D019899:Paracrine Communication; D058226:Plaque, Atherosclerotic; D000067996:RAW 264.7 Cells; D011994:Recombinant Proteins / Q000494:pharmacology; D012720:Severity of Illness Index; D015398:Signal Transduction; D014162:Transfection
chemical_list: C493410:FABP4 protein, human; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D011994:Recombinant Proteins
keywords: adipokine; atherosclerosis; coronary stenosis; fatty acid–binding protein 4; macrophage