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• W3016979633 abstract "Diabetic cardiomyopathy (DCM) accounts for increasing deaths of diabetic patients, and effective therapeutic targets are urgently needed. Myocardial lipotoxicity, which is caused by cardiac non-oxidative metabolic fatty acids and cardiotoxic fatty acid metabolites accumulation, has gained more attention to explain the increasing prevalence of DCM. However, whether mammalian Ste20-like kinase 1 (Mst1) plays a role in lipotoxicity in type 2 diabetes-induced cardiomyopathy has not yet been illustrated. Here, we found that Mst1 expression was elevated transcriptionally in the hearts of type 2 diabetes mellitus mice and palmitic acid-treated neonatal rat ventricular myocytes. Adeno-associated virus 9 (AAV9)-mediated Mst1 silencing in db/db mouse hearts significantly alleviated cardiac dysfunction and fibrosis. Notably, Mst1 knockdown in db/db mouse hearts decreased lipotoxic apoptosis and inflammatory response. Mst1 knockdown exerted protective effects through inactivation of MAPK/ERK kinase kinase 1 (MEKK1)/c-Jun N-terminal kinase (JNK) signaling pathway. Moreover, lipotoxicity induced Mst1 expression through promoting the binding of forkhead box O3 (FoxO3) and Mst1 promoter. Conclusively, we elucidated for the first time that Mst1 expression is regulated by FOXO3 under lipotoxicity stimulation and downregulation of Mst1 protects db/db mice from lipotoxic cardiac injury through MEKK1/JNK signaling inhibition, indicating that Mst1 abrogation may be a potential treatment strategy for DCM in type 2 diabetic patients. • A novel Mst1 transcription factor in cardiomyocyte, FOXO3, is identified. • Mst1 knockdown alleviates type 2 diabetes mellitus-induced cardiomyopathy. • Mst1 knockdown inhibits lipotoxicity-related myocardial inflammation and apoptosis. • Mst1 knockdown exerts its protective effects through MEKK1/JNK inhibition." @default.
• W3016979633 created "2020-04-24" @default.
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• W3016979633 date "2020-08-01" @default.
• W3016979633 modified "2023-10-18" @default.
• W3016979633 title "Mst1 knockdown alleviates cardiac lipotoxicity and inhibits the development of diabetic cardiomyopathy in db/db mice" @default.
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• W3016979633 doi "https://doi.org/10.1016/j.bbadis.2020.165806" @default.
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