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

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 FceR1-deficient mice, blunted foam cell formation and signaling in IgE-activated macrophages from Nhe1-deficient mice, immunocomplex formation of Nhe1 and FceR1 in IgE-activated macrophages, and Nhe1-FceR1 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. Na+-H+ exchanger 1 (Nhe1) regulates extracellular pH by extruding protons in exchange for extracellular Na+ . Here, Liu et al. show that Nhe1 promotes the development and acidification of atherosclerotic lesions and that pH-sensitive probes can be used to monitor plaque growth and acidification.