Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice

Hashimoto, Toru; Ichiki, Toshihiro; Watanabe, Aya; Hurt-Camejo, Eva; Michaëlsson, Erik; Ikeda, Jiro; Inoue, Emiko; Matsuura, Hirohide; Tokunou, Tomotake; Kitamoto, Shiro; Sunagawa, Kenji

doi:10.1016/j.vph.2014.03.006

Cited by 34 publications

(32 citation statements)

References 47 publications

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“…Consistent with the notion that the cholinergic anti-inflammatory pathway inhibits inflammation, we found that a7nAChR-knockout mice had higher clinical arthritis scores and more joint destruction compared to wild-type mice, as well as higher plasma levels of TNF and monocyte chemoattractant protein-1 levels [64]. The effect of stimulation of the cholinergic anti-inflammatory pathway was also evaluated in other animal models of chronic inflammation [65][66][67]. Atherosclerotic plaque formation was decreased upon AR-R17779 treatment associated with decreased expression of IL-1 and IL-6 in the aorta [65].…”

Section: Influence Of the Autonomic Nervous System On Chronic Inflammsupporting

confidence: 80%

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

et al. 2017

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Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune‐mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so‐called cholinergic anti‐inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL‐6 production and improved RA disease severity, even in some patients with therapy‐resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.

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Section: Influence Of the Autonomic Nervous System On Chronic Inflammsupporting

confidence: 80%

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

et al. 2017

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“…40 AR-R17779, another α7nAChR agonist, suppresses atherosclerosis and Ang II-induced aortic aneurysm formation in apolipoprotein E-deficient mice. 41 Another interesting issue is the endogenous ligand for α7nAChR in VSMCs. The well-accepted endogenous ligand for α7nAChR is acetylcholine.…”

Section: Discussionmentioning

confidence: 99%

“…The cells up to passage number 8 were used in the study. 40 The rat and mouse VSMCs were isolated and cultured using a standard enzymatic digestion 41 technique. [2] Animals were sacrificed with an overdose of pentobarbital sodium (100 mg/kg) 42 by intra-peritoneal injection before the aorta was excised.…”

mentioning

confidence: 99%

α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II–Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide–Dependent SIRT1 Activity

Huang

et al. 2016

ATVB

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Objective-α7 nicotinic acetylcholine receptor (α7nAChR) is a subtype of nAChR and has been reported to be involved in hypertension end-organ damage.In this study, we tested the role of α7nAChR in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). Approach and Results-Expression of α7nAChR was not influenced by Ang II. Ang II induced remarkable senescent phenotypes in rodent and human VSMCs, including increased senescence-associated β-galactosidase activity, phosphorylation of H2A.X Ser139, phosphorylation of Chk1 Ser317, reduced replication, and downregulation of proliferating cell nuclear antigen. Activation of α7nAChR with a selective agonist PNU-282987 blocked Ang II-induced senescence in cultured VSMCs. Moreover, PNU-282987 treatment attenuated the Ang II infusion-induced VSMC senescence in wildtype but not in α7nAChR −/− mice. PNU-282987 reduced the Ang II-enhanced reactive oxygen species, lipid peroxidation, and the expression of NADPH oxidase 1, NADPH oxidase 4, and p22 phox in cultured VSMCs isolated from wild-type but not in α7nAChR −/− mice. Furthermore, PNU-282987 diminished Ang II-induced prosenescence signaling pathways, including p53, acetyl-p53, p21, and p16 INK4a. Finally, although α7nAChR activation by PNU-282987 did not affect the Ang II-induced downregulation of sirtuin 1 (SIRT1), it significantly increased intracellular NAD + levels, and thereby enhanced SIRT1 activity in an AMP-dependent protein kinase-independent manner. Depletion of SIRT1 by knockdown or SIRT1 inhibitor EX527 abrogated the antisenescence effect of α7nAChR against Ang II. Conclusions-Our

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“…In addition, activation of the autonomic nervous system, both centrally and via afferent pathways, activates efferent neuronal circuits, including the cholinergic anti-inflammatory reflex (Tracey, 2009). Although this systems has potent immune-modulatory properties, its direct implication in atherosclerosis development and progression remains unresolved (Johansson et al, 2014;Hashimoto et al, 2014;Kooijman et al, 2015a,b). Nevertheless, the immune reflex and neuroendocrine control of metabolic pathways are clearly contributing factors in stress-mediated pathologies, as for example reviewed by Kibler et al (2014).…”

Section: Stress and Cardiovascular Disease: The Major Systems Involvedmentioning

confidence: 99%

Acute and chronic psychological stress as risk factors for cardiovascular disease: Insights gained from epidemiological, clinical and experimental studies

Lagraauw

Kuiper

Bot

2015

Brain, Behavior, and Immunity

200

131

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Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice

Cited by 34 publications

References 47 publications

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II–Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide–Dependent SIRT1 Activity

Acute and chronic psychological stress as risk factors for cardiovascular disease: Insights gained from epidemiological, clinical and experimental studies

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