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Theranostics 2020; 10(12):5276-5289. doi:10.7150/thno.42470 This issue Cite

Research Paper

Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis

Wei Qin1,2, Longyin Zhang2,3, Zhange Li2, Dan Xiao2, Yue Zhang2, Haiying Zhang2, Justine Nyakango Mokembo2, Seth Mikaye Monayo2, Nabanit Kumar Jha2, Philipp Kopylov4, Dmitri Shchekochikhin4, Yong Zhang2,5✉

1. School of Pharmacy, Jining Medical University, Rizhao, Shandong, China
2. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
3. Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
4. Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
5. Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, Heilongjiang, China

✉ Corresponding author: Yong Zhang, Department of Pharmacology, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongjiang, China. Tel: 86-451-86671354, Fax: 86-451-86669482, E-mail: hmuzhangyongcom

Citation:
Qin W, Zhang L, Li Z, Xiao D, Zhang Y, Zhang H, Mokembo JN, Monayo SM, Jha NK, Kopylov P, Shchekochikhin D, Zhang Y. Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis. Theranostics 2020; 10(12):5276-5289. doi:10.7150/thno.42470. https://www.thno.org/v10p5276.htm
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Abstract

Graphic abstract

Rationale: Nicotine exposure via cigarette smoking is strongly associated with atherosclerosis. However, the underlying mechanisms remain poorly understood. The current study aimed to identify whether endothelial to mesenchymal transition (EndMT) contributes to nicotine-induced atherosclerosis.

Methods: ApoE-/- mice were administered nicotine in their drinking water for 12 weeks. The effects of nicotine on EndMT were determined by immunostaining on aortic root and RNA analysis in aortic intima. In vitro nicotine-treated cell model was established on human aortic endothelial cells (HAECs). The effects of nicotine on the expression of EndMT-related markers, ERK1/2 and Snail were quantified by real-time PCR, western blot and immunofluorescent staining.

Results: Nicotine treatment resulted in larger atherosclerotic plaques in ApoE-/- mice. The vascular endothelial cells from nicotine-treated mice showed mesenchymal phenotype, indicating EndMT. Moreover, nicotine-induced EndMT process was accompanied by cytoskeleton reorganization and impaired barrier function. The α7 nicotine acetylcholine receptor (α7nAChR) was highly expressed in HAECs and its antagonist could effectively relieve nicotine-induced EndMT and atherosclerotic lesions in mice. Further experiments revealed that ERK1/2 signaling was activated by nicotine, which led to the upregulation of Snail. Blocking ERK1/2 with inhibitor or silencing Snail by small interfering RNA efficiently preserved endothelial phenotype upon nicotine stimulation.

Conclusion: Our study provides evidence that EndMT contributes to the pro-atherosclerotic property of nicotine. Nicotine induces EndMT through α7nAChR-ERK1/2-Snail signaling in endothelial cells. EndMT may be a therapeutic target for smoking-related endothelial dysfunction and cardiovascular disease.

Keywords: nicotine, atherosclerosis, EndMT, α7nAChR, Snail

Citation styles

APA
Qin, W., Zhang, L., Li, Z., Xiao, D., Zhang, Y., Zhang, H., Mokembo, J.N., Monayo, S.M., Jha, N.K., Kopylov, P., Shchekochikhin, D., Zhang, Y. (2020). Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis. Theranostics, 10(12), 5276-5289. https://doi.org/10.7150/thno.42470.

ACS
Qin, W.; Zhang, L.; Li, Z.; Xiao, D.; Zhang, Y.; Zhang, H.; Mokembo, J.N.; Monayo, S.M.; Jha, N.K.; Kopylov, P.; Shchekochikhin, D.; Zhang, Y. Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis. Theranostics 2020, 10 (12), 5276-5289. DOI: 10.7150/thno.42470.

NLM
Qin W, Zhang L, Li Z, Xiao D, Zhang Y, Zhang H, Mokembo JN, Monayo SM, Jha NK, Kopylov P, Shchekochikhin D, Zhang Y. Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis. Theranostics 2020; 10(12):5276-5289. doi:10.7150/thno.42470. https://www.thno.org/v10p5276.htm

CSE
Qin W, Zhang L, Li Z, Xiao D, Zhang Y, Zhang H, Mokembo JN, Monayo SM, Jha NK, Kopylov P, Shchekochikhin D, Zhang Y. 2020. Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis. Theranostics. 10(12):5276-5289.

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