Characterization of an Aging-Based Diagnostic Gene Signature and Molecular Subtypes With Diverse Immune Infiltrations in Atherosclerosis

Abstract

Objective: Advancing age is a major risk factor of atherosclerosis (AS). Nevertheless, the mechanism underlying this phenomenon remains indistinct. Herein, this study conducted a comprehensive analysis of the biological implications of aging-related genes in AS.Methods: Gene expression profiles of AS and non-AS samples were curated from the GEO project. Differential expression analysis was adopted for screening AS-specific aging-related genes. LASSO regression analysis was presented for constructing a diagnostic model, and the discriminatory capacity was evaluated with ROC curves. Through consensus clustering analysis, aging-based molecular subtypes were conducted. Immune levels were estimated based on the expression of HLAs, immune checkpoints, and immune cell infiltrations. Key genes were then identified via WGCNA. The effects of CEBPB knockdown on macrophage polarization were examined with western blotting and ELISA. Furthermore, macrophages were exposed to 100 mg/L ox-LDL for 48 h to induce macrophage foam cells. After silencing CEBPB, markers of cholesterol uptake, esterification and hydrolysis, and efflux were detected with western blotting.Results: This study identified 28 AS-specific aging-related genes. The aging-related gene signature was developed, which could accurately diagnose AS in both the GSE20129 (AUC = 0.898) and GSE43292 (AUC = 0.685) datasets. Based on the expression profiling of AS-specific aging-related genes, two molecular subtypes were clustered, and with diverse immune infiltration features. The molecular subtype–relevant genes were obtained with WGCNA, which were markedly associated with immune activation. Silencing CEBPB triggered anti-inflammatory M2-like polarization and suppressed foam cell formation.Conclusion: Our findings suggest the critical implications of aging-related genes in diagnosing AS and modulating immune infiltrations.

Identification of immune-related biomarkers and construction of regulatory network in patients with atherosclerosis

“…Synthetic lesions such as mass metabolism disorders and release of inflammatory factors may cause a variety of disorders, such as stroke, coronary artery disease (CAD), peripheral artery disease (PAD), and other cerebrovascular diseases [3,4]. Among them, stroke and coronary heart disease are considered to be the most common in the world [5]. Atherosclerotic is an important risk factor for these diseases.…”

Immune landscape and regulatory mechanisms in human atherosclerotic coronary plaques: Evidence from single-cell and bulk transcriptomics

“…CEBPB could regulate the expression of genes involved in immune and inflammatory responses [ 69 ]. The inhibition of CEBPB has recently been shown to prevent foam cell formation and atherosclerosis development [ 70 , 71 ], and CEBPB participates in the transcriptional and epigenetic regulation of macrophages in atherosclerosis [ 72 ]. CEBPB also combines with CCL2 and initiates the process of atherosclerosis [ 73 ].…”

Identification of immune infiltration-related biomarkers in carotid atherosclerotic plaques

“…They demonstrated that T cells and myeloid cells account for a large proportion of atherosclerotic immune cells and that macrophages and dendritic cells (DCs) revealed differential enrichments in the CAPs and control groups 13 . By using WGCNA, Zhao et al detected an age-associated gene as a biomarker of CAPs , and in vitro experiments suggest that the gene CEBPB participates in the progression of CAPs 33 . The aforementioned studies aimed to describe the change in the abundance of 24 immune cell types in atherosclerotic tissues; however, unlike previous research, we aimed to identify differential genes associated with the change in the abundance of immune cells.…”