RESUMO
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-1ß, 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.
Assuntos
Anti-Inflamatórios/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Piperazinas/uso terapêutico , Tiazóis/uso terapêutico , Animais , Cardiomiopatias/epidemiologia , Cardiomiopatias/patologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Fibrose/patologia , Células HEK293 , Humanos , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , NF-kappa B/metabolismo , Obesidade/complicações , Ratos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismoRESUMO
In the title compound, C(33)H(25)F(2)NO(2), the acenaphthene ring system forms dihedral angles of 50.93â (14) and 36.89â (14)° with the benzene rings. The pyrrolidine and cyclo-penta-none rings adopt envelope (with the N atom as the flap) and twisted conformations, respectively. In the crystal, C-Hâ¯O and C-Hâ¯F inter-actions link the mol-ecules.
