TY - JOUR
T1 - Na+-H+ exchanger 1 determines atherosclerotic lesion acidification and promotes atherogenesis
AU - Liu, Cong Lin
AU - Zhang, Xian
AU - Liu, Jing
AU - Wang, Yunzhe
AU - Sukhova, Galina K.
AU - Wojtkiewicz, Gregory R.
AU - Liu, Tianxiao
AU - Tang, Rui
AU - Achilefu, Samuel
AU - Nahrendorf, Matthias
AU - Libby, Peter
AU - Guo, Junli
AU - Zhang, Jin Ying
AU - Shi, Guo Ping
N1 - Funding Information:
The authors thank Ms. Eugenia Shvartz for her technical assistance and Ms. Chelsea Swallom for her editorial assistance. This study is supported by grants from the Finance Science and Technology Projects of Hainan Province (ZDYF2018102 to J.G.), the National Natural Science Foundation of China (81770487, 81460042 to J.G.; 81570274 and 81870328 to J.-Y.Z), and the National Heart, Lung, and Blood Institute (HL60942, HL123568 to G.-P.S.; HL34636, HL80472 to P.L.), the National Institute of Neurological Disorders and Stroke (AG058670 to G.-P.S.), and the National Cancer Institute (CA171651 to S.A.). C.-L.L. (17POST33670564) and X.Z. (18POST34050043) are supported by the American Heart Association Postdoctoral Fellowship.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-11983-3
DO - 10.1038/s41467-019-11983-3
M3 - Article
C2 - 31484936
AN - SCOPUS:85071737053
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3978
ER -