钠氢交换蛋白 1 决定动脉粥样硬化病变的酸化并促进动脉粥样硬化形成。

Na-H exchanger 1 determines atherosclerotic lesion acidification and promotes atherogenesis.

机构信息

Department of Cardiology, Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

出版信息

Nat Commun. 2019 Sep 4;10(1):3978. doi: 10.1038/s41467-019-11983-3.

The pH in atherosclerotic lesions varies between individuals. IgE activates macrophage Na-H exchanger (Nhe1) and induces extracellular acidification and cell apoptosis. Here, we show that the pH-sensitive pHrodo probe localizes the acidic regions in atherosclerotic lesions to macrophages, IgE, and cell apoptosis. In Apoe mice, Nhe1-deficiency or anti-IgE antibody reduces atherosclerosis and blocks lesion acidification. Reduced atherosclerosis in Apoe mice receiving bone marrow from Nhe1- or IgE receptor FcεR1-deficient mice, blunted foam cell formation and signaling in IgE-activated macrophages from Nhe1-deficient mice, immunocomplex formation of Nhe1 and FcεR1 in IgE-activated macrophages, and Nhe1-FcεR1 colocalization in atherosclerotic lesion macrophages support a role of IgE-mediated macrophage Nhe1 activation in atherosclerosis. Intravenous administration of a near-infrared fluorescent pH-sensitive probe LS662, followed by coregistered fluorescent molecular tomography-computed tomography imaging, identifies acidic regions in atherosclerotic lesions in live mice, ushering a non-invasive and radiation-free imaging approach to monitor atherosclerotic lesions in live subjects.

动脉粥样硬化病变中的 pH 值因人而异。IgE 会激活巨噬细胞 Na-H 交换器（Nhe1），并诱导细胞外酸化和细胞凋亡。在这里，我们发现 pH 敏感型 pHrodo 探针将动脉粥样硬化病变中的酸性区域定位到巨噬细胞、IgE 和细胞凋亡中。在 Apoe 小鼠中，Nhe1 缺陷或抗 IgE 抗体可减少动脉粥样硬化并阻止病变酸化。从 Nhe1 缺陷型巨噬细胞中，Apoe 小鼠接受 Nhe1 或 IgE 受体 FcεR1 缺陷型骨髓后，动脉粥样硬化减少，泡沫细胞形成和 IgE 激活的巨噬细胞信号减弱，IgE 激活的巨噬细胞中 Nhe1 和 FcεR1 的免疫复合物形成以及动脉粥样硬化病变巨噬细胞中的 Nhe1-FcεR1 共定位，支持 IgE 介导的巨噬细胞 Nhe1 激活在动脉粥样硬化中的作用。静脉内给予近红外荧光 pH 敏感探针 LS662，然后进行荧光分子断层扫描-计算机断层扫描成像，可在活鼠中识别动脉粥样硬化病变中的酸性区域，为在活体动物中监测动脉粥样硬化病变提供了一种非侵入性、无辐射的成像方法。