The Role and Mechanism of SIRT6 in Regulating Phenotype Transformation of Vascular Smooth Muscle Cells in Abdominal Aortic Aneurysm.

Xiaomei Guan,Jianlei Ji,Meiling Xu,Jun Li,Hai Xin

doi:10.1155/2022/3200798

Xiaomei Guan, Jianlei Ji + Show 3 more

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https://doi.org/10.1155/2022/3200798

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Abstract

Background Data mining of current gene expression databases has not been previously performed to determine whether sirtuin 6 (SIRT6) expression participates in the pathological process of abdominal aortic aneurysm (AAA). The present study was aimed at investigating the role and mechanism of SIRT6 in regulating phenotype transformation of vascular smooth muscle cells (VSMC) in AAA. Methods Three gene expression microarray datasets of AAA patients in the Gene Expression Omnibus (GEO) database and one dataset of SIRT6-knockout (KO) mice were selected, and the differentially expressed genes (DEGs) were identified using GEO2R. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of both the AAA-related DEGs and the SIRT6-related DEGs were conducted. Results GEO2R analysis showed that the expression of SIRT6 was downregulated for three groups and upregulated for one group in the three datasets, and none of them satisfied statistical significance. There were top 5 DEGs (KYNU, NPTX2, SCRG1, GRK5, and RGS5) in both of the human AAA group and SIRT6-KO mouse group. Top 25 ontology of the SIRT6-KO-related DEGs showed that several pathways including tryptophan catabolic process to kynurenine and negative regulation of cell growth were enriched in the tissues of thickness aortic wall biopsies of AAA patients. Conclusions Although SIRT6 mRNA level itself did not change among AAA patients, SIRT6 may play an important role in regulating several signaling pathways with significant association with AAA, suggesting that SIRT6 mRNA upregulation is a protective factor for VSMC against AAA.

Highlights

Data mining of current gene expression databases has not been previously performed to determine whether sirtuin 6 (SIRT6) expression participates in the pathological process of abdominal aortic aneurysm (AAA)
We found that nine biological processes (BP), one cellular components (CC), and one molecular functions (MF) were enriched in both of the human AAA group and SIRT6-KO mouse group
After knocking out the GATA5 in mouse endothelial cells, a gene related to blood pressure regulation, the GATA5-KO mice developed vascular endothelial dysfunction due to the destruction of normal endothelial signal transduction [25], and it was found that SIRT6 promoted the expression levels of GATA5 [26]

Summary

Introduction

Data mining of current gene expression databases has not been previously performed to determine whether sirtuin 6 (SIRT6) expression participates in the pathological process of abdominal aortic aneurysm (AAA). The main initiating factor of aortic aneurysm formation is the transformation of VSMCs from the physiological contraction phenotype (differentiation) to pathological synthesis and inflammatory state [4, 5]. This process involves the coordinated downregulation of smooth muscle contraction gene expression and contractility, as well as the production of matrix metalloproteinases (MMPs) and proteoglycans, leading to the degradation of the extracellular matrix, weakening of the aortic wall, and eventually rupture [6, 7]

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