PMID- 32320827 OWN - NLM STAT- MEDLINE DCOM- 20210104 LR - 20211204 IS - 1879-260X (Electronic) IS - 0925-4439 (Linking) VI - 1866 IP - 8 DP - 2020 Aug 1 TI - Mst1 knockdown alleviates cardiac lipotoxicity and inhibits the development of diabetic cardiomyopathy in db/db mice. PG - 165806 LID - S0925-4439(20)30151-4 [pii] LID - 10.1016/j.bbadis.2020.165806 [doi] AB - 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. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Xiong, Zhenyu AU - Xiong Z AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. FAU - Li, Yueyang AU - Li Y AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Zhao, Zhengqing AU - Zhao Z AD - Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai, China. FAU - Zhang, Yan AU - Zhang Y AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Man, Wanrong AU - Man W AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Lin, Jie AU - Lin J AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Dong, Yuan AU - Dong Y AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Liu, Liyuan AU - Liu L AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Wang, Bo AU - Wang B AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Wang, Huan AU - Wang H AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Guo, Baolin AU - Guo B AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Li, Congye AU - Li C AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Li, Fei AU - Li F AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: lifei01@fmmu.edu.cn. FAU - Wang, Haichang AU - Wang H AD - Heart Hospital, Xi'an International Medical Center, Xi'an, China. Electronic address: wanghc@fmmu.edu.cn. FAU - Sun, Dongdong AU - Sun D AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: wintersun3@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200419 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 RN - 0 (Fatty Acids) RN - 0 (Forkhead Box Protein O3) RN - 0 (FoxO3 protein, mouse) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (macrophage stimulating protein) RN - 67256-21-7 (Hepatocyte Growth Factor) RN - EC 2.7.1.- (Stk4 protein, mouse) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1) SB - IM MH - Animals MH - Animals, Newborn MH - Apoptosis/genetics MH - Diabetes Mellitus, Experimental/*genetics/metabolism/pathology/therapy MH - Diabetes Mellitus, Type 2/genetics/metabolism/pathology/therapy MH - Diabetic Cardiomyopathies/*genetics/metabolism/pathology/prevention & control MH - Fatty Acids/metabolism/*toxicity MH - Forkhead Box Protein O3/agonists/*genetics/metabolism MH - Gene Expression Regulation MH - Hepatocyte Growth Factor MH - Humans MH - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*genetics/metabolism MH - MAP Kinase Kinase Kinase 1/antagonists & inhibitors/*genetics/metabolism MH - Male MH - Membrane Potential, Mitochondrial/drug effects MH - Mice MH - Mice, Transgenic MH - Mitochondria/drug effects/metabolism/pathology MH - Myocytes, Cardiac/drug effects/metabolism/pathology MH - Oxidation-Reduction MH - Primary Cell Culture MH - Promoter Regions, Genetic MH - Protein Serine-Threonine Kinases/antagonists & inhibitors/*genetics/metabolism MH - Proto-Oncogene Proteins MH - RNA, Small Interfering/genetics/metabolism MH - Rats MH - Signal Transduction OTO - NOTNLM OT - Diabetic cardiomyopathy OT - Lipotoxicity OT - Mammalian sterile 20-like kinase 1, Mst1 OT - Type 2 diabetes mellitus COIS- Declaration of competing interest The authors declare that there is no conflict of interest associated with this manuscript. EDAT- 2020/04/23 06:00 MHDA- 2021/01/05 06:00 CRDT- 2020/04/23 06:00 PHST- 2020/01/24 00:00 [received] PHST- 2020/03/26 00:00 [revised] PHST- 2020/04/14 00:00 [accepted] PHST- 2020/04/23 06:00 [pubmed] PHST- 2021/01/05 06:00 [medline] PHST- 2020/04/23 06:00 [entrez] AID - S0925-4439(20)30151-4 [pii] AID - 10.1016/j.bbadis.2020.165806 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Basis Dis. 2020 Aug 1;1866(8):165806. doi: 10.1016/j.bbadis.2020.165806. Epub 2020 Apr 19.