From the Department of Cardiology, Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, China (C.-L.L., Y.W., J.-Y.Z., X.W., G.-P.S.).
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (C.-L.L., X.L., Y.W., Z.D., T.L., G.K.S., P.L., G.-P.S.).
Hypertension. 2020 Jul;76(1):87-100. doi: 10.1161/HYPERTENSIONAHA.119.14485. Epub 2020 Jun 1.
IgE-mediated activation of Nhe1 (Na-H exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)-induced AAA in Nhe1-insufficient mice and littermates tested Nhe1 activity in experimental AAA, because mice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions from mice, such acidic areas were much smaller in lesions from mice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.
IgE 介导的 Nhe1（Na-H 交换器-1）激活诱导主动脉细胞细胞外酸化并促进细胞凋亡。pH 敏感探针 pHrodo 在人及鼠腹主动脉瘤（AAA）病变中巨噬细胞聚集、IgE 表达和细胞凋亡的位置识别酸性区域。在 Nhe1 不足的 小鼠和 同窝仔鼠的 Ang II（血管紧张素 II）诱导的 AAA 中测试了 Nhe1 活性，因为 小鼠出现共济失调和癫痫样发作并早期死亡。Nhe1 不足降低了 AAA 的发生率和大小、病变巨噬细胞和 T 细胞的聚集、胶原沉积、弹性蛋白片段化、细胞凋亡、平滑肌细胞丢失和 MMP（基质金属蛋白酶）活性。Nhe1 不足还降低了血压和血浆凋亡标志物 TCTP（翻译控制肿瘤蛋白），但不影响血浆 IgE。虽然 pHrodo 将酸性区域定位于 小鼠 AAA 病变中的巨噬细胞簇、IgE 表达和细胞凋亡，但 小鼠病变中的此类酸性区域要小得多。AAA 病变中巨噬细胞中 Nhe1-FcεR1 的共定位支持 IgE 介导的 Nhe1 激活的作用。明胶酶谱分析、免疫印迹和实时聚合酶链反应分析表明，Nhe1 不足降低了 MMP 活性、半胱氨酸组织蛋白酶表达、IgE 诱导的凋亡和 NF-κB 在巨噬细胞中的激活，并阻断了 IgE 诱导的内皮细胞粘附分子表达。近红外荧光探针（LS662）与完整主动脉的荧光反射成像一起显示，Nhe1 不足的 小鼠 AAA 病变中的酸度降低。本研究揭示了人及鼠 AAA 病变中富含巨噬细胞、IgE 表达和细胞凋亡的区域的细胞外酸度，并确立了 Nhe1 在 AAA 发病机制中的直接作用。
