脂毒性
内分泌学
内科学
糖尿病性心肌病
安普克
心肌细胞
心功能曲线
心肌病
AMP活化蛋白激酶
蛋白激酶A
基因剔除小鼠
生物
医学
激酶
心力衰竭
胰岛素抵抗
糖尿病
细胞生物学
受体
作者
Yasuhide Kuwabara,Takahiro Horie,Osamu Baba,Shin Watanabe,Masataka Nishiga,Shunsuke Usami,Masayasu Izuhara,Tetsushi Nakao,Tomohiro Nishino,Kinya Otsu,Toru Kita,Takeshi Kimura,Koh Ono
出处
期刊:Circulation Research
[Ovid Technologies (Wolters Kluwer)]
日期:2015-01-16
卷期号:116 (2): 279-288
被引量:175
标识
DOI:10.1161/circresaha.116.304707
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI