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.
Keywords:
Diabetic cardiomyopathy; Lipotoxicity; Mammalian sterile 20-like kinase 1, Mst1; Type 2 diabetes mellitus.
Copyright © 2020 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Apoptosis / genetics
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Diabetes Mellitus, Experimental / genetics*
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Experimental / therapy
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Diabetes Mellitus, Type 2 / therapy
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Diabetic Cardiomyopathies / genetics*
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Diabetic Cardiomyopathies / metabolism
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Diabetic Cardiomyopathies / pathology
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Diabetic Cardiomyopathies / prevention & control
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Fatty Acids / metabolism
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Fatty Acids / toxicity*
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Forkhead Box Protein O3 / agonists
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Forkhead Box Protein O3 / genetics*
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Forkhead Box Protein O3 / metabolism
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Gene Expression Regulation
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Hepatocyte Growth Factor
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / genetics*
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase Kinase 1 / genetics*
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MAP Kinase Kinase Kinase 1 / metabolism
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Male
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Mice, Transgenic
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / pathology
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Myocytes, Cardiac / pathology
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Oxidation-Reduction
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Primary Cell Culture
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Signal Transduction
Substances
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Fatty Acids
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Forkhead Box Protein O3
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FoxO3 protein, mouse
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Proto-Oncogene Proteins
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RNA, Small Interfering
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macrophage stimulating protein
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Hepatocyte Growth Factor
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Stk4 protein, mouse
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1