Abstract
In macrophages the α7 nicotinic acetylcholine receptor (α7nAChR) modulates production of inflammatory cytokines, cholesterol accumulation and lipoprotein uptake. Recently, our laboratory showed that selective stimulation of the α7nAChR protects macrophages from apoptosis, an effect that is absent in α7nAChR-deficient macrophages. All these observations are suggestive of a potential role of macrophage α7nAChR in atherosclerosis. Mouse models of the disease with bone marrow deletion of α7nAChR represent an attractive approach to address the in vivo relevance of these in vitro findings. However, recent studies that focused on the impact of hematopoietic deficiency of α7nAChR on early atherosclerotic lesions of low density lipoprotein receptor knockout (LDLRKO) mice, yielded controversial results. The question also remained whether macrophage α7nAChR modulates the characteristics of advanced lesions. Here we used LDLR knockout mice transplanted with bone marrow from wild-type or α7nAChR knockout animals to revisit the effect of hematopoietic deficiency of α7nAChR on early lesions and to examine, for the first time, its impact on advanced plaques. Aortic sinus atherosclerotic lesions were analyzed following 8 and 14 weeks on a high fat diet. Early lesions in mice with α7nAChR deficient bone marrow were not different from those in control animals. However, advanced lesions of mice with bone marrow deletion of α7nAChR exhibited reduction in size, macrophage content and cell proliferation. These studies are the first in examining the impact of hematopoietic deficiency of α7nAChR on the characteristics of advanced atherosclerotic lesions in a mouse model of the disease and provide novel evidence underscoring a potential pro-atherogenic role of macrophage α7nAChR.
Highlights
The α7 nicotinic acetylcholine receptor (α7nAChR) is a ligand gated, non-selective cation channel with homopentameric arrangement which exhibits relatively high permeability to calcium compared to other nAChRs [1]
In this study we examined the effects of macrophage deficiency of α7nAChR on the characteristics of early and advanced stage atherosclerotic lesions in low density lipoprotein receptor knockout (LDLRKO) mice
Whereas early stage lesions in LDLRKO mice with α7nAChR deficient bone marrow were not different from those in control animals, bone marrow deficiency of α7nAChR had a clear favorable effect on advanced stages, as evidenced by a marked reduction in size, macrophage content and cell proliferation in lesions of mice maintained on a fourteen week high fat diet
Summary
The α7 nicotinic acetylcholine receptor (α7nAChR) is a ligand gated, non-selective cation channel with homopentameric arrangement which exhibits relatively high permeability to calcium compared to other nAChRs [1]. Besides its canonical localization and functions in the central and peripheral nervous systems, the α7nAChR is expressed in non-neuronal cells including endothelial cells, lymphocytes and macrophages [2,3,4,5]. The potential anti-inflammatory role of macrophage α7nAChR was further examined in peritoneal macrophages derived from a mouse model of atherosclerosis with global deficiency of α7nAChR [11]. These in vitro studies indicated that α7nAChR may contribute to regulation of macrophage cholesterol metabolism and lipoprotein uptake [11], and this is suggestive of a potential role of macrophage α7nAChR in atherogenesis, those findings were not validated by in vivo studies
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