title: Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice.
abstract: Circulating and myocardial expressions of receptor activator of nuclear factor-κb ligand and osteoprotegerin are activated in heart failure; however, it remains to be determined their pathophysiological roles on left ventricular structure and function in interaction with renin-angiotensin system. We conducted experiments using 8-week-old osteoprotegerin(-/-) mice and receptor activator of nuclear factor-κb ligand-transgenic mice to assess whether they affect the angiotensin II-induced left ventricular remodeling. Subcutaneous infusion of angiotensin II to osteoprotegerin(-/-) mice progressed the eccentric hypertrophy, resulting in left ventricular systolic dysfunction for 28 days, and this was comparable with wild-type mice, showing concentric hypertrophy, irrespective of equivalent elevation of systolic blood pressure. The structural alteration was associated with reduced interstitial fibrosis, decreased procollagen α1 and syndecan-1 expressions, and the increased number of apoptotic cells in the left ventricle, compared with wild-type mice. In contrast, angiotensin II infusion to the receptor activator of nuclear factor-κb ligand-transgenic mice revealed the concentric hypertrophy with preserved systolic contractile function. Intraperitoneal administration of human recombinant osteoprotegerin, but not subcutaneous injection of anti-receptor activator of nuclear factor-κb ligand antibody, to the angiotensin II-infused osteoprotegerin(-/-) mice for 28 days ameliorated the progression of heart failure without affecting systolic blood pressure. These results underscore the biological activity of osteoprotegerin in preserving myocardial structure and function during the angiotensin II-induced cardiac hypertrophy, independent of receptor activator of nuclear factor-κb ligand activity. In addition, the antiapoptotic and profibrotic actions of osteoprotegerin that emerged from our data might be involved in the mechanisms.
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.). ttsuruda@med.miyazaki-u.ac.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tsuruda
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sekita-Hatakeyama
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Yilin
authors.initials: Y
authors.lastname: Hao
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Sumiharu
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Syuji
authors.initials: S
authors.lastname: Kurogi
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Midori
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Taro
authors.initials: T
authors.lastname: Funamoto
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sekimoto
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Kinta
authors.initials: K
authors.lastname: Hatakeyama
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Etsuo
authors.initials: E
authors.lastname: Chosa
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Johji
authors.initials: J
authors.lastname: Kato
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Asada
authors.affiliation: From the Department of Internal Medicine, Circulatory and Body Fluid Regulation (T.T., Y.S.-H., Y.H., S.S., K.K.), Division of Orthopaedic Surgery, Department of Medicine of Sensory and Motor Organs (S.K., T.F., T.S., E.C.), Department of Pathology (Y.A.), Frontier Science Research Center (J.K.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry, Matsumoto Dental University, Nagano, Japan (M.N., N.U.); and Department of Diagnostic Pathology, Nara Medical University, Nara, Japan (K.H.).
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D054143:Heart Failure, Systolic / Q000188:drug therapy* / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053244:Osteoprotegerin / Q000172:deficiency*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D053244:Osteoprotegerin; D000804:Angiotensin II
keywords: angiotensin II; apoptosis; fibrosis; hypertension; hypertrophy