Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.
Department of Cardiology, The First Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China.
Shock. 2019 Mar;51(3):372-380. doi: 10.1097/SHK.0000000000001132.
This study tested the hypothesis that CD44 is involved in the development of cardiac fibrosis via angiotensin II (Ang II) AT1 receptor-stimulated TNFα/NFκB/IκB signaling pathways. Study was conducted in C57BL/6 wild type and CD44 knockout mice subjected to Ang II infusion (1,000 ng/kg/min) using osmotic minipumps up to 4 weeks or with gastric gavage administration of the AT1 receptor blocker, telmisartan at a dose of 10 mg/kg/d. Results indicated that Ang II enhances expression of the AT1 receptor, TNFα, NFκB, and CD44 as well as downregulates IκB. Further analyses revealed that Ang II increases macrophage migration, augments myofibroblast proliferation, and induces vascular/interstitial fibrosis. Relative to the Ang II group, treatment with telmisartan significantly reduced expression of the AT1 receptor and TNFα. These changes occurred in coincidence with decreased NFκB, increased IκB, and downregulated CD44 in the intracardiac vessels and intermyocardium. Furthermore, macrophage migration and myofibroblast proliferation were inhibited and fibrosis was attenuated. Knockout of CD44 did not affect Ang II-stimulated AT1 receptor and modulated TNFα/NFκB/IκB signaling, but significantly reduced macrophage/myofibroblast-mediated fibrosis as identified by less extensive collagen-rich area. These results suggest that the AT1 receptor is involved in the development of cardiac fibrosis by stimulating TNFα/NFκB/IκB-triggered CD44 signaling pathways. Knockout of CD44 blocked Ang II-induced cell migration/proliferation and cardiac fibrosis. Therefore, selective inhibition of CD44 may be considered as a potential therapeutic target for attenuating Ang II-induced deleterious cardiovascular effects.
本研究旨在验证假说，即 CD44 通过血管紧张素 II（Ang II）AT1 受体刺激 TNFα/NFκB/IκB 信号通路参与心肌纤维化的发展。研究在 C57BL/6 野生型和 CD44 敲除小鼠中进行，采用渗透微型泵向小鼠输注 Ang II（1000ng/kg/min）长达 4 周，或用 AT1 受体阻滞剂替米沙坦（剂量为 10mg/kg/d）进行胃灌胃给药。结果表明，Ang II 增强了 AT1 受体、TNFα、NFκB 和 CD44 的表达，同时下调了 IκB 的表达。进一步的分析显示，Ang II 增加了巨噬细胞的迁移，增强了肌成纤维细胞的增殖，并诱导了血管/间质纤维化。与 Ang II 组相比，替米沙坦治疗显著降低了 AT1 受体和 TNFα 的表达。这些变化与 NFκB 减少、IκB 增加和血管内及心肌内 CD44 下调同时发生。此外，巨噬细胞迁移和肌成纤维细胞增殖受到抑制，纤维化减轻。CD44 敲除不影响 Ang II 刺激的 AT1 受体，并调节 TNFα/NFκB/IκB 信号，但显著减少了由巨噬细胞/肌成纤维细胞介导的纤维化，表现为胶原丰富区面积减少。这些结果表明，AT1 受体通过刺激 TNFα/NFκB/IκB 触发的 CD44 信号通路参与心肌纤维化的发展。CD44 敲除阻断了 Ang II 诱导的细胞迁移/增殖和心脏纤维化。因此，选择性抑制 CD44 可能被视为减轻 Ang II 诱导的心血管不良作用的潜在治疗靶点。
