Compound c17 alleviates inflammatory cardiomyopathy in streptozotocin-induced diabetic mice by targeting MyD88.
Compound c17 alleviates inflammatory cardiomyopathy in streptozotocin-induced diabetic mice by targeting MyD88.
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DOI：
10.1016/j.intimp.2023.110863
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发表时间：
2023-09
影响因子：
5.6
通讯作者：
Qianhui Zhang;Weiwei Zhu;Shuaijie Lou;Hongdan Bao;Yafen Zhou;Zhaohong Cai;Jiaxi Ye;Yaqian Cui;Min-xiu Wang;Leiming Jin;Guang Liang;Wu Luo;Yi Wang
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文献类型：
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作者：
Qianhui Zhang;Weiwei Zhu;Shuaijie Lou;Hongdan Bao;Yafen Zhou;Zhaohong Cai;Jiaxi Ye;Yaqian Cui;Min-xiu Wang;Leiming Jin;Guang Liang;Wu Luo;Yi Wang
BackgroundDiabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and is associated with increased morbidity and mortality due to cardiac dysfunction. Chronic inflammation plays a significant role in the development of DCM, making it a promising target for novel pharmacological strategies. Our previous study has synthesized a novel compound, c17, which exhibited strong anti-inflammatory activity by specifically targeting to myeloid differentiation primary response 88 (MyD88). In this study, we evaluated the therapeutic effect of c17 in DCM.MethodsThe small molecular selective MyD88 inhibitor, c17, was used to evaluate the effect of MyD88 on DCM in both high concentration of glucose- and palmitic acid-stimulated macrophages and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice.ResultsThe treatment of c17 in T1DM mice resulted in improved heart function and reduced cardiac hypertrophy, inflammation and fibrogenesis. RNA sequencing analysis of the heart tissues revealed that c17 effectively suppressed the inflammatory response by regulating the MyD88-dependent pathway. Co-immunoprecipitation experiments further confirmed that c17 disrupted the interaction between MyD88 and Toll-like receptor 4 (TLR4), consequently inhibiting downstream NF-κB activation.In vitrostudies demonstrated that c17 exhibited similar anti-inflammatory activity by targeting MyD88 in macrophages, which are the primary regulators of cardiac inflammation. Furthermore, conditioned medium derived from c17-treated macrophages showed reduced capacity to induce hypertrophy, pro-fibrotic reactions, and secondary inflammation in cardiomyocytes.ConclusionsIn conclusion, the small-molecule MyD88 inhibitor, c17, effectively combated the inflammatory DCM, therefore could be a potential candidate for the treatment of this disease.
