MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-κB signaling pathway
MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-κB signaling pathway
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MD2通过直接结合Ang II并激活TLR4/NF-kappa B信号通路介导血管紧张素II诱导的心脏炎症和重塑
DOI：
10.1007/s00395-016-0599-5
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发表时间：
2017-01-01
影响因子：
9.5
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Han, Jibo;Zou, Chunpeng;Liang, Guang
血管紧张素 II (Ang II) 会诱导心脏炎症和重塑。新的证据表明，Ang II 可能利用 Toll 样受体 4 (TLR4) 信号通路来介导促炎症和促纤维化活性。然而，人们对确切的机制知之甚少。骨髓分化 2 (MD2) 是一种与 TLR4 物理结合的分子，赋予脂多糖反应性，也可能参与介导 Ang II 的作用。我们假设 MD2 在局部 Ang II 诱导的心脏炎症和重塑中发挥重要作用，抑制 MD2 可以减轻 Ang II 诱导的心脏功能障碍。使用特定的小分子 MD2 阻滞剂 L6H21 和 MD2 敲除小鼠，我们发现 MD2 缺乏可显着减轻皮下注射 Ang II 的小鼠的心脏炎症以及随后的纤维化、肥大和功能障碍。在大鼠心肌细胞样 H9c2 细胞以及大鼠原代心肌细胞中，通过 L6H21 或 siRNA 敲低抑制 MD2 可抑制 Ang II 诱导的 TLR4 信号通路激活，包括 MyD88 募集，并减少心肌细胞肥大和基质蛋白表达。 Ang II 的这些促炎活性不依赖于 AT1 受体。最后，我们证明了 Ang II 和 MD2 蛋白之间通过 Arg-90、Glu-92 和 Asp-100 上的氢键直接相互作用。 Ang II 通过直接结合 MD2、激活 MD2/TLR4 复合物并招募 MyD88 来产生炎症反应和心脏重塑。 MD2可能是Ang II介导的心脏炎症和重塑的新治疗靶点。
Angiotensin II (Ang II) induces cardiac inflammation and remodeling. Emerging evidence indicates that Ang II may utilize the Toll-like receptor 4 (TLR4) signaling pathway in mediating pro-inflammatory and profibrotic activities. However, the precise mechanism is poorly understood. Myeloid differentiation 2 (MD2), a molecule that physically binds to TLR4, confers lipopolysaccharide responsiveness and may also be involved in mediating the actions of Ang II. We hypothesize that MD2 plays an essential role in cardiac inflammation and remodeling induced by local Ang II, and inhibition of MD2 can attenuate Ang II-induced cardiac dysfunction. Using a specific small molecule MD2 blocker L6H21 and the MD2 knockout mice, we show that MD2 deficiency significantly reduces cardiac inflammation and subsequent fibrosis, hypertrophy, and dysfunction in mice challenged with subc2utaneous injection of Ang II. In rat cardiomyocyte-like H9c2 cells as well as rat primary cardiomyocytes, inhibition of MD2 by L6H21 or siRNA knockdown suppressed the Ang II-induced TLR4 signaling pathway activation including MyD88 recruitment, and reduced cardiomyocyte hypertrophy and matrix protein expression. These pro-inflammatory activities of Ang II were independent of the 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. Ang II produces an inflammatory response and cardiac remodeling by directly binding to MD2, activating MD2/TLR4 complex, and recruiting MyD88. MD2 may be a new therapeutic target for Ang II-mediated cardiac inflammation and remodeling.