Yasuhide Kuwabara1, Takahiro Horie1, Osamu Baba1, Shin Watanabe1, Masataka Nishiga1, Shunsuke Usami1, Masayasu Izuhara1, Tetsushi Nakao1, Tomohiro Nishino1, Kinya Otsu1, Toru Kita1, Takeshi Kimura1, Koh Ono2. 1. 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.). 2. 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.
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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 DMmouse 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: Gábor Koncsos; Zoltán V Varga; Tamás Baranyai; Kerstin Boengler; Susanne Rohrbach; Ling Li; Klaus-Dieter Schlüter; Rolf Schreckenberg; Tamás Radovits; Attila Oláh; Csaba Mátyás; Árpád Lux; Mahmoud Al-Khrasani; Tímea Komlódi; Nóra Bukosza; Domokos Máthé; László Deres; Monika Barteková; Tomáš Rajtík; Adriana Adameová; Krisztián Szigeti; Péter Hamar; Zsuzsanna Helyes; László Tretter; Pál Pacher; Béla Merkely; Zoltán Giricz; Rainer Schulz; Péter Ferdinandy Journal: Am J Physiol Heart Circ Physiol Date: 2016-08-12 Impact factor: 4.733