Role and therapeutic potential of gelsolin in atherosclerosis

https://doi.org/10.1016/j.yjmcc.2023.03.012Get rights and content

Highlights

  • This paper introduces the comprehensive structure, function, and distribution of GSN in the body.

  • Evidence gathered for link between GSN and pathological basis of atherosclerosis.

  • On the basis of research, it is speculated that the target of GSN on atherosclerosis.

  • Proposes the possibility of GSN as a biomarker for atherosclerosis.

Abstract

Atherosclerosis is the major pathophysiological basis of a variety of cardiovascular diseases and has been recognized as a lipid-driven chronic inflammatory disease. Gelsolin (GSN) is a member of the GSN family. The main function of GSN is to cut and seal actin filaments to regulate the cytoskeleton and participate in a variety of biological functions, such as cell movement, morphological changes, metabolism, apoptosis and phagocytosis. Recently, more and more evidences have demonstrated that GSN is Closely related to atherosclerosis, involving lipid metabolism, inflammation, cell proliferation, migration and thrombosis. This article reviews the role of GSN in atherosclerosis from inflammation, apoptosis, angiogenesis and thrombosis.

Introduction

With the economy and society developing, cardiovascular diseases have become an important reason for threatening human life and health. There are about 17 million people die from cardiovascular diseases each year, and it is estimated to exceed 23 million until 2030 [1]. Atherosclerosis is a lipid-driven inflammatory disease and constitutes the pathological basis of the most cardiovascular diseases such as myocardial infarction and stroke. Currently, many theories are proposed to explain the pathogenesis of atherosclerosis, among which lipid infiltration is the most widely accepted. In the beginning, a variety of risk factors, such as smoking, hemodynamic abnormalities, mechanical injury, carbon monoxide, hypoxia, catecholamine, and hyperlipidemia, cause endothelial damage and increase the expression of cellular adhesion molecules. Macrophages then enter the subendothelial space through damaged vessels to ingest the lipid material and form lipid-rich foam cells, eventually promoting atherosclerotic plaque formation. Inflammation can promote pathological processes such as macrophage adhesion, local cell apoptosis and accelerate the development of atherosclerosis.

Gelsolin (GSN), a major member of the GSN family, can affect cell movement, morphology, metabolism, apoptosis, phagocytosis and other functions by cleaving terminal actin. Many studies have shown that GSN is related to the risk factors of atherosclerosis, such as inflammation, lipid metabolism, and angiogenesis [[2], [3], [4]]. There is also a positive correlation between plasma GSN (pGSN) levels and High-density lipoprotein cholesterol (HDLsingle bondC) concentration [5].In addition, compared with normal tissue, the expression of GSN in arteriosclerosis is significantly reduced [3]. These findings suggest that GSNs play an important role in the occurrence and development of atherosclerosis. In this overview, we summarized the current knowledge about the pathophysiological and etiological roles of GSN in atherosclerosis and tried to provide a basis for future investigation and therapeutic intervention.

Section snippets

Structure

GSN, an 82-84 kDa protein, was firstly discovered in rabbit pulmonary macrophages in 1979 [6]. GSN contains two homologous parts: N-terminal and C-terminal domain. Every domain is composed of three parts, called G1-G3 and G4-G6, respectively. The G1-G3 belongs to the N-terminal half of GSN and its activation is independent of Ca2+, while the domain G4-G6 belongs to the C-terminal half and its activation depends on Ca2+. These two domains are connected and can be cut by apoptosis effector

GSN-mediated signal transductions

GSN regulates many kinds of cellular signal transduction in vivo, among which the PLC-γ/EGFR and Ras/PI3K/Rac pathways are typical [[22], [23], [24]].

Pathological bases of atherosclerosis

The occurrence and development of atherosclerosis is a continuous process, and there are many theories about its development, such as thrombosis theory, inflammation theory, lipid infiltration theory and injury theory. Among them, the theory of lipid infiltration is the most widely studied. According to the theory of lipid infiltration, atherosclerosis mainly lies in the formation of subintimal foam cells after the arterial endothelium is damaged by various mechanisms.

Foam cell formation is an

Potential mechanism of GSN on atherosclerosis

The occurrence and development of atherosclerosis is a complicated process involving numerous mechanisms. Both inflammation and foam cell formation play a critical role in the pathogenesis of atherosclerosis. Other contributors include endothelial cell proliferation and migration, angiogenesis, and apoptosis. GSN is involved in the development of atherosclerosis through multiple pathways.

Potential therapeutic strategies of GSN

cGSN is expressed in whole-body cells, mainly in platelets, macrophages, and neutrophils. pGSN is mainly produced and released into circulation by muscle cells. It is suggested that GSN plays an important role in atherosclerosis. Therefore, targeting GSN may be an attractive therapeutic strategy for atherosclerosis. There is increasing evidence that miRNAs play an important role in atherosclerosis. For instance, miR-200a and miR-21 are down-regulated in atherosclerotic plaques, and their

Conclusions and prospects

GSN, a member of the actin cleavage protein family, is mainly responsible for actin cleavage, capping and nucleation, blocking the elongation of actin and remodeling the cytoskeleton. In addition to the above functions, GSN can also regulate signal pathways, act as transcription factors, and play a variety of functions, such as regulating inflammation, apoptosis, cell proliferation and migration. The relationship between GSN and atherosclerosis is complex, which is mainly reflected in the

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

The authors gratefully acknowledge the financial support from the Natural Science Foundation of Hunan Province (2022JJ30535).

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    These authors contributed equally to this work.

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