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

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.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…Finally, NHE1 hyperactivity has recently been shown to be involved not only in the onset of cancer all along the digestive tract, from the degeneration of Barret’s esophagus into esophageal cancer to the relationship of inflammatory bowel disease and colon cancer, but also in the onset and promotion of atherosclerosis. This latter feature makes a hyperactive NHE also highly important outside the oncological setting [ 57 , 58 , 59 ].…”

Deficiency of immunoglobulin E protects mice from experimental abdominal aortic aneurysms

“…Deficiency of TLR4 protected mice from Ang‐II perfusion‐induced AAA . We recently showed that Nhe1‐deficiency also reduced diet‐induced atherosclerosis and Ang‐II perfusion‐induced AAA formation in mice (Shi, unpublished observation). We showed that IgE activities in activating foam cell formation and associated signaling transduction (p‐AKT, p‐PI3K, and p‐mTOR), and in inducing protease expression and apoptosis were blocked in macrophages from Apoe −/− Nhe1 +/− mice .…”

“…We showed that IgE activities in activating foam cell formation and associated signaling transduction (p-AKT, p-PI3K, and p-mTOR), and in inducing protease expression and apoptosis were blocked in macrophages from Apoe −/− Nhe1 +/− mice. 28 IgE-induced macrophage expression of IL6 and monocyte chemoattractant protein-1 (MCP-1) and macrophage apoptosis were also muted in cells from TLR4-deficient Tlr4 −/− mice. 27 Therefore, the activities of TLR4 and Nhe1 may also be affected in Fcεr1a −/− mice, thereby contributing to reduced AAA in these mice.…”

“…Although not tested, IgE may activate the MAPK signaling pathways in other aortic wall inflammatory and vascular cells that express FcεR1. 17,27,28 This mechanism may involve not only IL6, but also other MAPK signaling-associated pro-inflammatory cytokines, chemokines, and proteases from inflammatory and vascular cells, thereby damaging the aortic wall. For example, IL6 and MAPK signaling stimulate MMP and cysteinyl cathepsin expression in macrophages and fibroblasts.…”

“…Deficiency of FcεR1, TLR4, or Nhe1 blocked IgE activity in inducing macrophage expressions of cytokines and chemokines and macrophage and vascular cell apoptosis. 27,28 Fibrinogen ligand or disintegrin rhodostomin activates Nhe1 by forming complexes with integrin α IIb β 3 , followed by activating the sodium-calcium exchanger NCX1. 29 Activation of Nhe1 promotes the opening of integrin α v β 3 headpiece, thereby increasing cell adhesion and migration.…”