PMID- 36241098 OWN - NLM STAT- MEDLINE DCOM- 20221206 LR - 20221208 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 206 DP - 2022 Dec TI - Blockage of MyD88 in cardiomyocytes alleviates cardiac inflammation and cardiomyopathy in experimental diabetic mice. PG - 115292 LID - S0006-2952(22)00386-0 [pii] LID - 10.1016/j.bcp.2022.115292 [doi] AB - Hyperglycemia-associated inflammation contributes to diabetic cardiomyopathy. Myeloid differentiation primary-response protein 88 (MyD88) is an adapter protein of many Toll-like receptors (TLRs) and is recruited to TLRs to initiate inflammatory response in endotoxin-activated innate immunity. However, the role of MyD88 in diabetic cardiomyopathy is unknown. We examined the role and mechanism of MyD88 in inflammatory heart injuries in diabetes and identified MyD88 as a potential target for the treatment of diabetic cardiomyopathy. In this study, we first found that MyD88 expression was increased in cardiomyocytes of diabetic mouse hearts. In cultured cardiomyocytes, MyD88 inhibition either by siRNA or by small-molecular inhibitor LM8 markedly blocked TLR4-MyD88 complex formation, reduced pro-inflammatory mitogen-activated protein kinases/nuclear factor-kappaB (MAPKs/NF-kappaB) cascade activation and decreased pro-inflammatory cytokine expression under high glucose condition. Moreover, pharmacologic inhibition of MyD88 by LM8 showed significantly anti-inflammatory, anti-hypertrophic and anti-fibrotic effects in the hearts of both type 1 and type 2 diabetic mice. These beneficial effects of MyD88 inhibition were correlated to the reduced activation of TLR4-MyD88-MAPKs/NF-kappaB signaling pathways in the hearts. Taken together, MyD88 in cardiomyocytes mediates diabetes-induced cardiac inflammatory injuries and pharmacological inhibition of MyD88 shows significantly cardioprotective effects, indicating MyD88 as a potential therapeutic target for diabetic cardiomyopathy. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Luo, Wu AU - Luo W AD - Department of Cardiology and Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Wu, Gaojun AU - Wu G AD - Department of Cardiology and Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Chen, Xiaojun AU - Chen X AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Zhang, Qiuyan AU - Zhang Q AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Zou, Chunpeng AU - Zou C AD - Department of Ultrasonography, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. FAU - Wang, Jun AU - Wang J AD - Department of Cardiology, Wenzhou Central Hospital, Wenzhou 325035, Zhejiang, China. FAU - Liu, Jun AU - Liu J AD - Department of Cardiology and Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Chattipakorn, Nipon AU - Chattipakorn N AD - Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. FAU - Wang, Yi AU - Wang Y AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. FAU - Liang, Guang AU - Liang G AD - Department of Cardiology and Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China. Electronic address: liangguang@wmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221012 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (NF-kappa B) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (Toll-Like Receptor 4) RN - 0 (Toll-Like Receptors) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Myd88 protein, mouse) SB - IM MH - Mice MH - Animals MH - NF-kappa B/genetics/metabolism MH - Myeloid Differentiation Factor 88/genetics/metabolism MH - Myocytes, Cardiac/metabolism MH - Toll-Like Receptor 4/genetics/metabolism MH - *Diabetic Cardiomyopathies/drug therapy/metabolism MH - *Diabetes Mellitus, Experimental/metabolism MH - Signal Transduction MH - Toll-Like Receptors MH - Adaptor Proteins, Signal Transducing/metabolism MH - Inflammation/metabolism OTO - NOTNLM OT - Cardiomyocytes OT - Diabetic cardiomyopathy OT - Fibrosis OT - Inflammation OT - MyD88 COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/10/15 06:00 MHDA- 2022/12/07 06:00 CRDT- 2022/10/14 19:33 PHST- 2021/12/04 00:00 [received] PHST- 2022/10/03 00:00 [revised] PHST- 2022/10/03 00:00 [accepted] PHST- 2022/10/15 06:00 [pubmed] PHST- 2022/12/07 06:00 [medline] PHST- 2022/10/14 19:33 [entrez] AID - S0006-2952(22)00386-0 [pii] AID - 10.1016/j.bcp.2022.115292 [doi] PST - ppublish SO - Biochem Pharmacol. 2022 Dec;206:115292. doi: 10.1016/j.bcp.2022.115292. Epub 2022 Oct 12.