Lipid-related protein NECTIN2 is an important marker in the progression of carotid atherosclerosis: An intersection of clinical and basic studies

Shen Li; Yuan Gao; Ke Ma; Yanan Li; Chen Liu; Yingxue Yan; Weishi Liu; Hongbing Liu; Zhen Li; Bo Song; Yuming Xu; Zongping Xia

doi:10.2478/jtim-2021-0044

Lipid-related protein NECTIN2 is an important marker in the progression of carotid atherosclerosis: An intersection of clinical and basic studies

J Transl Int Med. 2021 Dec 31;9(4):294-306. doi: 10.2478/jtim-2021-0044. eCollection 2021 Dec 1.

Authors

Shen Li^{1

2}, Yuan Gao¹, Ke Ma³, Yanan Li^{1

2}, Chen Liu^{1

2}, Yingxue Yan^{1

2}, Weishi Liu^{1

2}, Hongbing Liu¹, Zhen Li³, Bo Song¹, Yuming Xu¹, Zongping Xia^{1

2}

Affiliations

¹ Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
² Department of Clinical Systems Biology Laboratories, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
³ Department of Vascular Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.

Abstract

Background: The nectin cell adhesion molecule 2 (NECTIN2) protein is a cell adhesion molecule involved in lipid metabolism. We aimed to explore the potential role of NECTIN2 in carotid atherosclerosis (CA).

Materials and methods: Patients who underwent carotid endarterectomy (CEA) at the First Affiliated Hospital of Zhengzhou University were enrolled in this study. APOE^-/- rats fed western or normal diet were used to model early pathological changes in CA. The relationship between patients' lipid indices and plaque severity was assessed using ordinal regression analysis. Mendelian randomisation (MR) analysis was used to determine the causal links between low-density lipoprotein cholesterol (LDL-C) and atherosclerosis. After matching analysis of the single-cell transcriptome and microarray data of carotid plaques, NECTIN2 was identified as a key factor affecting CA. The importance of NECTIN2 was further verified by immunofluorescence staining of CEA and APOE^-/- rat specimens.

Results: A total of 108 patients were included. The traditional lipid indices did not correlate significantly with the plaque severity (P > 0.05). NECTIN2 provided a strong causal link between LDL-C level and CA (MR effect size >0). Deep-sequencing data illustrated that NECTIN2 expression was cell specific. In early-stage CA, NECTIN2 expression was increased in endothelial cells; however, in advanced-stage CA, NECTIN2 was overexpressed in macrophages located in fibrous caps. APOE^-/- rat carotid artery and human carotid plaques modelled the entire atherosclerotic process, showing an upregulation of NECTIN2 expression in CA.

Conclusions: Lipid-related protein NECTIN2 is a potential marker in CA progression and can potentially be a new therapeutic target for clinical prevention.

Keywords: Mendelian randomisation; NECTIN2; atherosclerosis; deep sequencing; plaque; thrombectomy.