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

Cong-Lin Liu, Xian Zhang, Jing Liu, Yunzhe Wang, Galina K. Sukhova, Gregory R. Wojtkiewicz, Tianxiao Liu, Rui Tang, Samuel Achilefu, Matthias Nahrendorf, Peter Libby, Junli Guo (), Jin-Ying Zhang () and Guo-Ping Shi ()
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Cong-Lin Liu: the First Affiliated Hospital of Zhengzhou University
Xian Zhang: Brigham and Women’s Hospital and Harvard Medical School
Jing Liu: Brigham and Women’s Hospital and Harvard Medical School
Yunzhe Wang: the First Affiliated Hospital of Zhengzhou University
Galina K. Sukhova: Brigham and Women’s Hospital and Harvard Medical School
Gregory R. Wojtkiewicz: Harvard Medical School
Tianxiao Liu: Brigham and Women’s Hospital and Harvard Medical School
Rui Tang: Washington University School of Medicine
Samuel Achilefu: Washington University School of Medicine
Matthias Nahrendorf: Harvard Medical School
Peter Libby: Brigham and Women’s Hospital and Harvard Medical School
Junli Guo: Brigham and Women’s Hospital and Harvard Medical School
Jin-Ying Zhang: the First Affiliated Hospital of Zhengzhou University
Guo-Ping Shi: the First Affiliated Hospital of Zhengzhou University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11983-3

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