title: MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol.
abstract: BACKGROUND
  Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated.
  
  
  OBJECTIVE
  To clarify the role of miR-33 involved in heart failure.
  
  
  RESULTS
  We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33-deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice.
  
  
  CONCLUSIONS
  Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Masataka
authors.initials: M
authors.lastname: Nishiga
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horie
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Kuwabara
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Kazuya
authors.initials: K
authors.lastname: Nagao
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Osamu
authors.initials: O
authors.lastname: Baba
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Nakao
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishino
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Daihiko
authors.initials: D
authors.lastname: Hakuno
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakashima
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nishi
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Fumiko
authors.initials: F
authors.lastname: Nakazeki
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Yuya
authors.initials: Y
authors.lastname: Ide
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Koyama
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kimura
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Hanada
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Inada
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Koji
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan (M.N., T.H., Y.K., O.B., T.Nakao, T.Nishino, D.H., Y.N., H.N., F.N., Y.I., S.K., M.K., R.H., T.Kimura, K.O.); Department of Cardiovascular Center, Osaka Red Cross Hospital, Japan (K.N., T.I.); Department of Pharmacology, Kansai Medical University, Hirakata, Osaka, Japan (T.Nakamura); Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Japan (K.H.); Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University of Medicine, Indianapolis (S.J.C.); and Kobe City Medical Center General Hospital, Japan (T.Kita). kohono@kuhp.kyoto-u.ac.jp.
authors.forename: Koh
authors.initials: K
authors.lastname: Ono
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D002784:Cholesterol
keywords: atherosclerosis; fibroblasts; fibrosis; heart failure; microRNAs