MicroRNA-451 Exacerbates Lipotoxicity in Cardiac Myocytes and High-Fat Diet-Induced Cardiac Hypertrophy in Mice through Suppression of the LKB1/AMPK Pathway
Rationale: In some type 2 diabetes patients without hypertension, cardiac hypertrophy and attenuated cardiac function are observed, and this insult is termed "diabetic cardiomyopathy." To date, microRNA functions in diabetic cardiomyopathy remain to be elucidated.
Objective: To clarify the functions of microRNAs involved in diabetic cardiomyopathy caused by type 2 diabetes.
Methods and Results: C57BL/6 mice were fed a high-fat diet (HFD) for 20 weeks, which induced obesity and type 2 diabetes. MicroRNA microarray analyses and real-time PCR revealed that miR-451 levels were significantly increased in the type 2 diabetes mouse hearts. Because excess supply of saturated fatty acids is a cause of diabetic cardiomyopathy, we stimulated neonatal rat cardiac myocytes (NRCMs) 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 NRCMs. 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 NRCMs and Cab39 overexpression rescued the lipotoxicity. To clarify miR-451 functions in vivo, we generated cardiomyocyte-specific miR-451 knockout (miR-451 cKO) mice. HFD-induced cardiac hypertrophy and contractile reserves were ameliorated in miR-451 cKO mice compared with control mice. Protein levels of Cab39 and phosphorylated AMPK were increased and phosphorylated mammalian target of rapamycin (mTOR) was reduced in miR-451 cKO 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.
- Received July 1, 2014.
- Revision received October 23, 2014.
- Accepted October 30, 2014.