Invited commentaryThe role of nicotine in the pathogenesis of atherosclerosis
Section snippets
Pathogenesis of tobacco-related vascular disease
Smoking is a major preventable risk factor for atherosclerosis. Exposure to cigarette smoke activates a number of mechanisms predisposing to atherosclerosis, including thrombosis, insulin resistance and dyslipidemia, vascular inflammation, abnormal vascular growth and angiogenesis, as well as loss of endothelial homeostatic and regenerative functions [1], [2], [3]. The pathophysiologic mechanisms by which tobacco smoke accelerates vascular disease are manifold and complex, in part because the
Nicotine signaling in the vessel wall
The effects of nicotine on cells within the vessel wall are mediated by cholinergic receptors. There are two major types of cholinergic receptors, the muscarinic and the nicotinic [5]. Whereas acetylcholine stimulates both receptor types, nicotine preferentially stimulates the nicotinic receptor. The muscarinic receptors are 7-transmembrane spanning G protein-gated receptors. By contrast, the nicotinic acetylcholine receptors (nAChRs) are each composed of 5 subunits, arranged in a barrel-like
A new role for the “muscle type” nAChR in atherosclerosis
The “muscle-type” nAChR, first found in the neuromuscular junction of skeletal muscle, consists of the specific assembly of five polypeptide subunits (α1, β1, δ, and ɛ in a 2:1:1:1 ratio). These subunits have since been described in other cell types, including endothelial cells [13]. In this issue of Atherosclerosis, Zhang and colleagues provide evidence that the muscle-type nAChR may play a direct role in regulating vascular smooth muscle cell proliferation and migration. They first observed
Effect of α1-silencing on plaque cells and paracrine factors
During the development of the atherosclerotic lesion, proliferating vascular smooth muscle cells (vsmc; or a vsmc progenitor) migrate into the intima and undergo phenotypic modulation into myofibroblasts and osteoblast-like cells. There they elaborate extracellular matrix (collagen and osteopontin), and even take up lipid to resemble macrophage-derived foam cells. In this study, silencing of the α1 subunit was associated with an 80% reduction in myofibroblasts in the lesion, and a reduction in
Pathological neovascularization and the endothelial nAChR
This observation is consistent with the notion that plaque neovascularization is critically involved in plaque progression. In this regard, Judah Folkman's group showed that endostatin and other anti-angiogenic agents could block the progression of plaque growth in apolipoprotein (ApoE)-deficient mice [14]. Furthermore, inhibition of plaque angiogenesis reduced macrophage accumulation in the atheroma. In the cholesterol-fed rabbit model, Celletti et al. [15] found that vascular endothelial
Exploring the role of the nAChR in atherosclerosis
A number of interesting questions are raised by this article. Firstly, is there really a “muscle type” nAChR expressed by any cells in the vessel wall or atherosclerotic plaque? As previously mentioned, in the neuromuscular junction of the adult, these heteromeric receptors consist of β1, δ, and ɛ subunits as well as α1 subunits. Although the presence of the α1 subunit is consistent with the existence of a vascular “muscle-type” receptor, it is also possible that there is an atypical
Acknowledgements
This work was supported in part by grants from the National Institutes of Health (RC2HL103400, 1U01HL100397 and K12 HL087746), and by the Tobacco Related Disease Research Program of the University of California (18XT-0098). Dr. Cooke is an inventor on Stanford University patents related to therapeutic modulation of angiogenesis by agonists or inhibitors of the nACh receptors.
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