【摘 要】
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Objective: We hypothesize that MD2 plays an essential role in Ang Ⅱ-induced cardiac inflammation and remodeling,and inhibition of MD2 can attenuate heart failure related to increased local Ang Ⅱ level
【机 构】
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the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
【出 处】
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2016年浙江省医学会心电生理与起搏学术年会
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Objective: We hypothesize that MD2 plays an essential role in Ang Ⅱ-induced cardiac inflammation and remodeling,and inhibition of MD2 can attenuate heart failure related to increased local Ang Ⅱ level.Methods and Results: Using a specific small-molecular MD2 inhibitor L6H21 and the MD2 knockout mice,we found that MD2 blockage significantly reduced cardiac inflammation and subsequent injurious phenotypes including fibrosis,hypertrophy,remodeling,and dysfunctions,in mice suffered by a subcutaneous injection of Ang Ⅱ.In cardiac H9c2 cells and rat primary cardiomyocytes,inhibition of MD2 by L6H21 or siRNA knockdown suppressed the TLR4-MyD88-ERK/NF-κB pro-inflammatory signaling pathway activation,and reduced cardiomyocyte fibrosis and hypertrophy.Ang Ⅱ-induced inflammatory injury is independent on AT1 receptor.Finally,we demonstrated the direct interaction between Ang Ⅱ and MD2 protein via hydrogen bonds on Arg-90,Glu-92,and Asp-100.Conclusion: Ang Ⅱ directly binds to MD2 and then activates MD2/TLR4 complex and MyD88 recruitment,resulting in inflammatory response and cardiac remodeling.MD2 may be a new therapeutic target for Ang Ⅱ-mediated cardiac inflammation and remodeling.
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