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

Ming-Yow Hung; Yi-Hong Wu; Oluwaseun Adebayo Bamodu; Xi Chen; Yen-Kuang Lin; Patrick Hu; Nen-Chung Chang; Jong-Hwei Su Pang; Chi-Tai Yeh

doi:10.1016/j.freeradbiomed.2018.03.050

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

Free Radic Biol Med. 2018 May 20:120:266-276. doi: 10.1016/j.freeradbiomed.2018.03.050. Epub 2018 Mar 31.

Authors

Ming-Yow Hung¹, Yi-Hong Wu², Oluwaseun Adebayo Bamodu³, Xi Chen⁴, Yen-Kuang Lin⁵, Patrick Hu⁶, Nen-Chung Chang⁷, Jong-Hwei Su Pang⁸, Chi-Tai Yeh⁹

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan.
² Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
³ Department of Hematology and Oncology, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medical Research and Education, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan.
⁴ International Medical Center, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang Province, China.
⁵ Biostatistics Research Center, Taipei Medical University, Taipei, Taiwan.
⁶ International Cardiovascular Institute, Las Vegas, Nevada, USA; Department of Cardiology, Riverside Medical Clinic, Riverside, California, USA.
⁷ Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
⁸ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan. Electronic address: jonghwei@mail.cgu.edu.tw.
⁹ Department of Medical Research and Education, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan. Electronic address: ctyeh@s.tmu.edu.tw.

PMID: 29609021
DOI: 10.1016/j.freeradbiomed.2018.03.050

Abstract

Objective: Smoking and high-sensitivity C-reactive protein (hs-CRP) are risk factors for coronary artery spasm (CAS), which is characterized by the increased interleukin-6 (IL-6) level and monocyte counts; however, limited data are available regarding the role of cigarette-embedded nicotine in the modulation of monocytic inflammatory activity in CAS.

Approach: We investigated and elucidated the putative roles and associations of nicotine, monocytic IL-6, α7 nicotinic acetylcholine receptor (α7-nAChR), and CRP in CAS development.

Results: We demonstrated that a significantly increased α7-nAChR (p = 0.001) and IL-6 (p = 0.0036) messenger RNA (mRNA) expression in the serum of patients with CAS. Serum hs-CRP levels exhibited a strong positive correlation with the monocytic mRNA expression of α7-nAChR (r = 0.71, p < 0.001) and IL-6 (r = 0.49, p = 0.006). The α7-nAChR and IL-6 expression levels of the CAS group were also positively correlated (r = 0.63, p < 0.001). Compared with the untreated controls, THP-1 cells and patient-derived monocytes treated with different concentrations of CRP displayed significantly increased expression levels of α7-nAChR mRNA and protein (p = 0.0054), in a dose-dependent manner. We also demonstrated that compared with the IL-6 expression elicited by CRP alone (p = 0.0489), the CRP-induced rise in monocytic IL-6 mRNA and protein expression in the presence of nicotine (p = 0.0002), is mediated by α7-nAChR activation and the deregulation of the human p38 mitogen-activated protein kinases (MAPK) signaling pathway.

Conclusions: Our data demonstrate that the elevated monocytic IL-6 and α7-nAChR mRNA and protein expression levels are associated with the interaction between nicotine and CRP positively modulates CAS development. Our study suggests the potential role of α7-nAChR mRNA and/or protein expression as a diagnostic biomarker for CAS.

Keywords: Acute coronary syndrome; Coronary artery spasm; Inflammation; Monocyte-derived macrophages; Monocytes; Nicotine acetylcholine receptor; p38-MAPK; α7-nAChR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
C-Reactive Protein / metabolism
Cohort Studies
Coronary Vasospasm / metabolism*
Coronary Vasospasm / physiopathology
Female
Humans
Inflammation / metabolism
Interleukin-6 / metabolism
MAP Kinase Signaling System / drug effects
MAP Kinase Signaling System / physiology*
Male
Middle Aged
Monocytes / metabolism*
Nicotine / adverse effects
Nicotinic Agonists / adverse effects
Oxidative Stress / drug effects
Oxidative Stress / physiology*
Prospective Studies
Smoking / adverse effects
alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

IL6 protein, human
Interleukin-6
Nicotinic Agonists
alpha7 Nicotinic Acetylcholine Receptor
Nicotine
C-Reactive Protein