Activation of the monocytic α7 nicotinic acetylcholine receptor modulates oxidative stress and inflammation-associated development of coronary artery spasm via a p38 MAP-kinase signaling-dependent pathway

Hung, Ming-Yow; Wu, Yijing; Bamodu, Oluwaseun Adebayo; Chen, Xi; Lin, Yen‐Kuang; Hu, Patrick; Chang, Nen-Chung; Pang, Jong‐Hwei S.; Yeh, Chi‐Tai

doi:10.1016/j.freeradbiomed.2018.03.050

Cited by 12 publications

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“…Cholinergic signaling and nicotinic acetylcholine receptors (nAChRs) have recently gained focus in cardiovascular morbidity and mortality [ 11 , 12 ]. The α 7-nAChRs, encoded by the CHRNA7 gene, are of relevance in inflammation [ 9 ] and expressed by mononuclear inflammatory cells, including monocytes and monocyte-derived macrophages [ 13 , 14 ]. We previously demonstrated that the activation of monocytic α 7-nAChR exacerbated oxidative stress and promoted CAS through a p38 mitogen-activated protein kinase- (MAPK-) dependent mechanism [ 9 ], which is in line with the studies of the nicotinic atherogenic effects of nAChR [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…The α 7-nAChRs, encoded by the CHRNA7 gene, are of relevance in inflammation [ 9 ] and expressed by mononuclear inflammatory cells, including monocytes and monocyte-derived macrophages [ 13 , 14 ]. We previously demonstrated that the activation of monocytic α 7-nAChR exacerbated oxidative stress and promoted CAS through a p38 mitogen-activated protein kinase- (MAPK-) dependent mechanism [ 9 ], which is in line with the studies of the nicotinic atherogenic effects of nAChR [ 11 , 12 ]. Furthermore, the excessive vascular smooth muscle cell (VSMC) contraction in CAS has been related to Ras-homologous (Rho) A GTPase/Rho-kinase (ROCK1, ROCK2) pathway, which can induce inflammation and oxidative stress [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…The disproportionately large impact of Lp(a) on cardiovascular disease risk compared with low-density lipoprotein implies that additional pathogenic pathways need to be considered. Moreover, despite the implication of α 7-nAChR and Lp(a) in CAS and shared molecular mediators [ 7 – 9 , 20 ] between them, it remains undetermined whether CAS is due to the 2 conditions sharing common inflammatory factors or whether shared inflammatory factors provide the link. There is increasing evidence that blood monocyte function may be changed by dyslipidemia [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…Because nicotine is the major reinforcing component and psychoactive drug of tobacco smoke [ 25 ], both nicotine in the tobacco smoke [ 26 ] and endogenous acetylcholine may contribute to the CAS development. We previously demonstrated that activation of the monocytic α 7-nAChRs modulates oxidative stress and inflammation-associated development of CAS via a p38 MAP-kinase signaling-dependent pathway [ 9 ]. In addition, positive interactions exist among CRP, hemoglobin, and platelet in women with CAS, but not in men [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Apolipoprotein (a)/Lipoprotein(a)-Induced Oxidative-Inflammatory α7-nAChR/p38 MAPK/IL-6/RhoA-GTP Signaling Axis and M1 Macrophage Polarization Modulate Inflammation-Associated Development of Coronary Artery Spasm

Lin

Yeh

Kuo

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. Apolipoprotein (a)/lipoprotein(a) (Lp(a)), a major carrier of oxidized phospholipids, and α7-nicotinic acetylcholine receptor (α7-nAChR) may play an important role in the development of coronary artery spasm (CAS). In CAS, the association between Lp(a) and the α7-nAChR-modulated inflammatory macrophage polarization and activation and smooth muscle cell dysfunction remains unknown. Methods. We investigated the relevance of Lp(a)/α7-nAChR signaling in patient monocyte-derived macrophages and human coronary artery smooth muscle cells (HCASMCs) using expression profile correlation analyses, fluorescence-assisted cell sorting flow cytometry, immunoblotting, quantitative real-time polymerase chain reaction, and clinicopathological analyses. Results. There are increased serum Lp(a) levels (3.98-fold, p = 0.011 ) and macrophage population (3.30-fold, p = 0.013 ) in patients with CAS compared with patients without CAS. Serum Lp(a) level was positively correlated with high-sensitivity C-reactive protein ( r 2 = 0.48 , p < 0.01 ), IL-6 ( r 2 = 0.38 , p = 0.03 ), and α7-nAChR ( r 2 = 0.45 , p < 0.01 ) in patients with CAS, but not in patients without CAS. Compared with untreated or low-density lipoprotein- (LDL-) treated macrophages, Lp(a)-treated macrophages exhibited markedly enhanced α7-nAChR mRNA expression ( p < 0.01 ) and activity ( p < 0.01 ), in vitro and ex vivo. Lp(a) but not LDL preferentially induced CD80+ macrophage (M1) polarization and reduced the inducible nitric oxide synthase expression and the subsequent NO production. While shRNA-mediated loss of α7-nAChR function reduced the Lp(a)-induced CD80+ macrophage pool, both shRNA and anti-IL-6 receptor tocilizumab suppressed Lp(a)-upregulated α7-nAChR, p-p38 MAPK, IL-6, and RhoA-GTP protein expression levels in cultures of patient monocyte-derived macrophages and HCASMCs. Conclusions. Elevated Lp(a) levels upregulate α7-nAChR/IL-6/p38 MAPK signaling in macrophages of CAS patients and HCASMC, suggesting that Lp(a)-triggered inflammation mediates CAS through α7-nAChR/p38 MAPK/IL-6/RhoA-GTP signaling induction, macrophage M1 polarization, and HCASMC activation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Apolipoprotein (a)/Lipoprotein(a)-Induced Oxidative-Inflammatory α7-nAChR/p38 MAPK/IL-6/RhoA-GTP Signaling Axis and M1 Macrophage Polarization Modulate Inflammation-Associated Development of Coronary Artery Spasm

Lin

Yeh

Kuo

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…The major addictive bioactive component of cigarettes is nicotine, the bio-effects of which are mediated by nicotinic acetylcholine receptors (nAChRs) [17,18,19,20]. Among the various types of nAChRs, the oncogenic role of the α7-nAChR in several malignancies, including lung cancer [21], malignant pleural mesotheliomas [22], and breast cancer [23], has garnered increased interest.…”

Section: Introductionmentioning

confidence: 99%

Smoking as an Independent Risk Factor for Hepatocellular Carcinoma Due to the α7-Nachr Modulating the JAK2/STAT3 Signaling Axis

Lin

Chen

et al. 2019

JCM

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Background: Hepatocellular carcinoma (HCC) is a worldwide health problem. Currently, there is no effective clinical therapeutic strategy for HCC. Smoking is associated with several malignant diseases including cancers. Experimental approach: However, the impact of smoking on HCC is still unresolved. Retrospectively reviewed HCC patients diagnosed between 1 January 2010 and 31 December 2015 at Taipei Medical University-Shuang Ho Hospital (Ministry of Health and Welfare). We found that smoking was associated with a poor prognosis, especially recurrence and patient survival after curative surgery using a clinicopathological analysis. Results: Our univariate and multivariate analyses showed that the α7-nicotinic acetylcholine receptor (α7-nAChR) was an oncogene and risk factor for post-resection recurrence. The α7-nAChR was overexpressed in HCC tissues compared to their non-tumor counterparts. Silencing the α7-nAChR reduced the viability of HCC cells, suppressed cellular proliferation, attenuated migration and invasion, and diminished the tumor’s sphere-formation ability, with concurrent downregulation of expression levels of the TGR5, p-JAK2, p-STAT3 (Tyr705/Ser727), RhoA, ROCK1, MMP2, and MMP9 proteins. Furthermore, a positive correlation was found between α7-nAChR and JAK2 expressions (p = 0.01) in HCC specimens, as well as their membranous co-localization. Conclusion: Together, we demonstrated that the α7-nAChR may be an independent prognosticator of the progression and prognosis of HCC patients. These findings suggest that the α7-nAChR drives the progression and recurrence of HCC through JAK2/STAT3 signaling and is a novel target for anti-HCC therapy.

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An integral perspective of canonical cigarette and e-cigarette-related cardiovascular toxicity based on the adverse outcome pathway framework

Ding

Ren

Sun

et al. 2022

Journal of Advanced Research

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Activation of the monocytic α7 nicotinic acetylcholine receptor modulates oxidative stress and inflammation-associated development of coronary artery spasm via a p38 MAP-kinase signaling-dependent pathway

Cited by 12 publications

References 52 publications

Apolipoprotein (a)/Lipoprotein(a)-Induced Oxidative-Inflammatory α7-nAChR/p38 MAPK/IL-6/RhoA-GTP Signaling Axis and M1 Macrophage Polarization Modulate Inflammation-Associated Development of Coronary Artery Spasm

Apolipoprotein (a)/Lipoprotein(a)-Induced Oxidative-Inflammatory α7-nAChR/p38 MAPK/IL-6/RhoA-GTP Signaling Axis and M1 Macrophage Polarization Modulate Inflammation-Associated Development of Coronary Artery Spasm

Smoking as an Independent Risk Factor for Hepatocellular Carcinoma Due to the α7-Nachr Modulating the JAK2/STAT3 Signaling Axis

An integral perspective of canonical cigarette and e-cigarette-related cardiovascular toxicity based on the adverse outcome pathway framework

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