title: MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway.
abstract: BACKGROUND
  In some patients with type 2 diabetes mellitus (DM) without hypertension, cardiac hypertrophy and attenuated cardiac function are observed, and this insult is termed diabetic cardiomyopathy. To date, microRNA (miRNAs or miR) functions in diabetic cardiomyopathy remain to be elucidated.
  
  
  OBJECTIVE
  To clarify the functions of miRNAs involved in diabetic cardiomyopathy caused by type 2 DM.
  
  
  RESULTS
  C57BL/6 mice were fed a high-fat diet (HFD) for 20 weeks, which induced obesity and type 2 DM. miRNA microarray analyses and real-time polymerase chain reaction revealed that miR-451 levels were significantly increased in the type 2 DM mouse hearts. Because excess supply of saturated fatty acids is a cause of diabetic cardiomyopathy, we stimulated neonatal rat cardiac myocytes with palmitic acid and confirmed that miR-451 expression was increased in a dose- and time-dependent manner. Loss of miR-451 function ameliorated palmitate-induced lipotoxicity in neonatal rat cardiac myocytes. Calcium-binding protein 39 (Cab39) is a scaffold protein of liver kinase B1 (LKB1), an upstream kinase of AMP-activated protein kinase (AMPK). Cab39 was a direct target of miR-451 in neonatal rat cardiac myocytes and Cab39 overexpression rescued the lipotoxicity. To clarify miR-451 functions in vivo, we generated cardiomyocyte-specific miR-451 knockout mice. HFD-induced cardiac hypertrophy and contractile reserves were ameliorated in cardiomyocyte-specific miR-451 knockout mice compared with control mice. Protein levels of Cab39 and phosphorylated AMPK were increased and phosphorylated mammalian target of rapamycin (mTOR) was reduced in cardiomyocyte-specific miR-451 knockout mouse hearts compared with control mouse hearts.
  
  
  CONCLUSIONS
  Our results demonstrate that miR-451 is involved in diabetic cardiomyopathy through suppression of the LKB1/AMPK pathway.
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, Japan (T.Kita.).
authors.forename: Shin
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, Japan (T.Kita.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Usami
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, Japan (T.Kita.).
authors.forename: Masayasu
authors.initials: M
authors.lastname: Izuhara
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, Japan (T.Kita.).
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, 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, Kyoto, Japan (Y.K., T.H., O.B., S.W., M.N., S.U., M.I., T. Nakao, T. Nishino, T.Kimura., K.Ono.); Cardiovascular Division, The James Black Centre, King's College London, London, United Kingdom (K.Otsu.); and Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo Prefecture, Japan (T.Kita.). kohono@kuhp.kyoto-u.ac.jp.
authors.forename: Koh
authors.initials: K
authors.lastname: Ono
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D035683:MicroRNAs; C550758:Mirn451 microRNA, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; cardiomegaly; microRNAs; type 2 diabetes mellitus