Immunoglobulin E (IgE) associates with allergic responses, but we found that its serum levels are enhanced in patients with acute myocardial infarction or unstable angina pectoris;they are nearly double those in patients with stable angina pectoris or without coronary heart disease. Both IgE and its high-affinity receptor Fc?R1 were expressed highly in human atherosclerotic lesions, localized to areas rich in macrophages (M?), and colocalized to lesion smooth-muscle cells (SMCs) and endothelial cells (ECs). Preliminary experiments showed that in the absence of Fc?R1 ?-subunit, atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice developed 75% fewer lipid depositions in the thoracic-abdominal aorta and had a >50% reduction in atherosclerotic lesion sizes in the aortic arch, compared with Apoe-/- control mice. In vitro cell culture studies demonstrated that IgE induced activation of M?, SMC, and EC mitogen-activated protein kinase (MAPK) pathway, along with enhanced inflammatory molecule production and apoptosis. Surprisingly, IgE stimulated a complex formation between Fc?R1 ?-chain and Toll-like receptor 4 (TLR4). Both Fc?R1 ?-subunit and TLR4 are necessary for IgE-induced M? cytokine and chemokine expression and apoptosis. Furthermore, these activities of IgE on M? associate with activation of Na+-H+ exchanger NHE1, followed by extracellular pH reduction. These novel preliminary findings are consistent with prior observations that in human atherosclerotic lesions, apoptotic cells cluster around lipid-rich necrotic cores, where the pH values are significantly lower (pH 7.15?0.01) than in other areas of the same lesions (pH 7.55?0.32, P=0.0001). Therefore, we hypothesize that IgE contributes to atherosclerosis by regulating M?, vascular SMC, and EC inflammation and apoptosis, and that these processes depend on Fc?R1 and TLR4 interaction as well as on NHE1 activation. We propose two specific aims to test this hypothesis: 1). To examine the molecular mechanisms by which IgE stimulates M? and vascular SMC and EC inflammation and apoptosis. 2). To examine whether inhibition or deficiency of IgE or IgE receptor Fc?R1 reduces atherosclerosis, and to test the importance of IgE-mediated M? activation in atherogenesis. We anticipate that the experiments proposed in both aims will establish an important and novel role of IgE in M? and vascular cell pathobiology, and a direct participation of IgE in atherogenesis.
IgE is produced by plasma cells in response to allergic reactions. Recent discoveries of mast cell functions in atherosclerosis, and our preliminary studies of in vitro cell culture and in vivo mouse experimental atherosclerosis, prompted the hypothesis that IgE stimulates inflammatory cell and vascular cell inflammation and apoptosis, thereby promoting atherogenesis. These IgE activities are mediated by coordinate interactions between the IgE receptor Fc?R1 and TLR4, and via activation of the Na+-H+ exchanger NHE1. Deficiency or pharmacological inactivation of Fc?R1, TLR4, or NHE1 blocks IgE activities, and may thus reduce atherogenesis.
|Wang, Jing; Sukhova, Galina K; Liu, Jian et al. (2015) Cathepsin G deficiency reduces periaortic calcium chloride injury-induced abdominal aortic aneurysms in mice. J Vasc Surg 62:1615-24|
|Bot, Ilze; Shi, Guo-Ping; Kovanen, Petri T (2015) Mast cells as effectors in atherosclerosis. Arterioscler Thromb Vasc Biol 35:265-71|
|Xu, Junyan; Shi, Guo-Ping (2014) Vascular wall extracellular matrix proteins and vascular diseases. Biochim Biophys Acta 1842:2106-2119|
|Lafarge, Jean-Charles; Pini, Maria; Pelloux, Véronique et al. (2014) Cathepsin S inhibition lowers blood glucose levels in mice. Diabetologia 57:1674-83|
|Wang, Jing; Sjöberg, Sara; Tang, Ting-Ting et al. (2014) Cathepsin G activity lowers plasma LDL and reduces atherosclerosis. Biochim Biophys Acta 1842:2174-83|
|Xu, Na; Zhang, Yuan-Yuan; Lin, Yan et al. (2014) Increased levels of lysosomal cysteinyl cathepsins in human varicose veins: a histology study. Thromb Haemost 111:333-44|
|Wang, Jing; Lindholt, Jes S; Sukhova, Galina K et al. (2014) IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms. EMBO Mol Med 6:952-69|
|Hu, Lina; Cheng, Xian Wu; Song, Haizhen et al. (2014) Cathepsin K activity controls injury-related vascular repair in mice. Hypertension 63:607-15|
|Hua, Yinan; Xu, Xihui; Shi, Guo-Ping et al. (2013) Cathepsin K knockout alleviates pressure overload-induced cardiac hypertrophy. Hypertension 61:1184-92|
|He, Aina; Shi, Guo-Ping (2013) Mast cell chymase and tryptase as targets for cardiovascular and metabolic diseases. Curr Pharm Des 19:1114-25|
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