title: Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure.
abstract: Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti-placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Ayako
authors.initials: A
authors.lastname: Seno
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Yukiji
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsui
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Aya
authors.initials: A
authors.lastname: Okuda
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakano
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Nakada
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Takuya
authors.initials: T
authors.lastname: Kumazawa
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Taku
authors.initials: T
authors.lastname: Nishida
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Onoue
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Somekawa
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawata
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Rika
authors.initials: R
authors.lastname: Kawakami
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okura
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.).
authors.forename: Shiro
authors.initials: S
authors.lastname: Uemura
authors.affiliation: From the First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan (A.S., Y.T., M.M., A.O., T. Nakano, Y.N., T.K., H.N., T. Nishida, K.O., S.S., M.W., H.K., R.K., H.O., S.U., Y.S.); and Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan (T.K., Y.S.). saitonaramed@gmail.com.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D018709:Statistics, Nonparametric; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; C501163:Flt1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: chronic kidney disease; heart failure; hypertrophy/remodeling; monocyte chemoattractant protein-1; placental growth factor