Masato Furuhashi1, Takahiro Fuseya2, Masaki Murata2, Kyoko Hoshina2, Shutaro Ishimura2, Tomohiro Mita2, Yuki Watanabe2, Akina Omori2, Megumi Matsumoto2, Takeshi Sugaya2, Tsuyoshi Oikawa2, Junichi Nishida2, Nobuaki Kokubu2, Marenao Tanaka2, Norihito Moniwa2, Hideaki Yoshida2, Norimasa Sawada2, Kazuaki Shimamoto2, Tetsuji Miura2. 1. 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. 2. 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.).
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis.
OBJECTIVE: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. APPROACH AND RESULTS: 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. CONCLUSIONS:FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis.
Authors: Kelly J Shields; Kostas Verdelis; Michael J Passineau; Erin M Faight; Lee Zourelias; Changgong Wu; Rong Chong; Raymond L Benza Journal: Pulm Circ Date: 2016-12 Impact factor: 3.017
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311