Article

Compound LM9, a novel MyD88 inhibitor, efficiently mitigates inflammatory responses and fibrosis in obesity-induced cardiomyopathy

Authors: Xu-yong Zheng1,2, Chu-chu Sun3, Qian Liu1,2, Xiao-yao Lu1, Li-li Fu1, Guang Liang1, Xiu-hua Zhang2, Gao-zhi Chen1
1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
2 Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
3 The Third Affiliated Hospital of Wenzhou Medical University, Ruian 325200, China
Correspondence to: Xiu-hua Zhang: wzzhangxiuhua@126.com, Gao-zhi Chen: cgztc@163.com,
DOI: 10.1038/s41401-020-0410-x
Received: 7 November 2019
Accepted: 27 March 2020
Advance online: 27 April 2020

Abstract

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 obesityinduced cardiomyopathy, suggesting LM9 to be a promising therapeutic candidate drug for the obesity-related cardiac complications.
Keywords: MyD88; inflammation; obesity; cardiomyopathy; palmitic acid

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