Compound LM9, a novel MyD88 inhibitor, efficiently mitigates inflammatory responses and fibrosis in obesity-induced cardiomyopathy
Compound LM9, a novel MyD88 inhibitor, efficiently mitigates inflammatory responses and fibrosis in obesity-induced cardiomyopathy
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DOI：
10.1038/s41401-020-0410-x
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发表时间：
2020-04
影响因子：
8.2
通讯作者：
Xu-yong Zheng;Chunyan Sun;Qian Liu;Xiao-yao Lu;Li-li Fu;G. Liang;Xiu-hua Zhang;Gaozhi Chen
中科院分区：
文献类型：
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作者：
Xu-yong Zheng;Chunyan Sun;Qian Liu;Xiao-yao Lu;Li-li Fu;G. Liang;Xiu-hua Zhang;Gaozhi Chen
肥胖/高脂血症引起的心肌病发病机制复杂。肥胖通常与慢性低度炎症有关，并可能导致心肌纤维化和重构的发生和进展。TLR4/MyD88信号通路作为炎症的关键调控因子，在肥胖性心肌病的发病机制中起着重要作用。我们之前证明了LM9，一种新的MyD88抑制剂，通过抑制TLR4/MyD88复合物的形成，减轻了肥胖诱导的心肌病的炎症反应和纤维化。在本研究中，我们在体外和体内研究了LM9对肥胖性心肌病的保护作用。结果表明，LM9 （5,10 μM）可显著减轻小鼠腹膜巨噬细胞中棕榈酸（PA）诱导的炎症，其促炎基因包括TNF-α、IL-6、IL-1β和ICAM-1的表达降低。在心源性H9C2细胞中，LM9治疗抑制pa诱导的炎症、脂质积累和纤维化反应。此外，LM9处理还抑制pa激活的TLR4/MyD88/NF-κB信号通路。我们进一步发现，在HEK293细胞中，LM9处理阻断了TLR4/MyD88结合和MyD88同型二聚体的形成。在hfd喂养的小鼠中，给予LM9（5、10 mg/kg, ig，每隔一天，连续8周）剂量依赖性地减轻了心脏组织的炎症和纤维化，降低了血脂浓度。综上所述，本研究表明MyD88抑制剂LM9对肥胖引起的心肌病具有保护作用，提示LM9是一种有前景的治疗肥胖相关心脏并发症的候选药物。
Mechanisms of cardiomyopathy caused by obesity/hyperlipidemia are complicated. Obesity is usually associated with chronic low-grade inflammation and may lead to the onset and progression of myocardial fibrosis and remodeling. TLR4/MyD88 signaling pathway, as a key regulator of inflammation, plays an important role in the pathogenesis of obesity-induced cardiomyopathy. We previously demonstrated that LM9, a novel MyD88 inhibitor, attenuated inflammatory responses and fibrosis in obesity-induced cardiomyopathy by inhibiting the formation of TLR4/MyD88 complex. In this study, we investigated the protective effects of LM9 on obesity-induced cardiomyopathy in vitro and in vivo. We showed that LM9 (5, 10 μM) significantly attenuates palmitic acid (PA)-induced inflammation in mouse peritoneal macrophages, evidenced by decreased expression of proinflammatory genes including TNF-α, IL-6, IL-1β, and ICAM-1. In cardiac-derived H9C2 cells, LM9 treatment suppressed PA-induced inflammation, lipid accumulation, and fibrotic responses. In addition, LM9 treatment also inhibited PA-activated TLR4/MyD88/NF-κB signaling pathway. We further revealed in HEK293 cells that LM9 treatment blocked the TLR4/MyD88 binding and MyD88 homodimer formation. In HFD-fed mice, administration of LM9 (5, 10 mg/kg, ig, every other days for 8 weeks) dose-dependently alleviated inflammation and fibrosis in heart tissues and decreased serum lipid concentration. In conclusion, this study demonstrates that MyD88 inhibitor LM9 exerts protective effects against obesity-induced cardiomyopathy, suggesting LM9 to be a promising therapeutic candidate drug for the obesity-related cardiac complications.