Senescence-related epicardial adipocyte genes lead to immune infiltration and myocardial infarction progression

TL;DR

This study identifies genes in heart fat tissue linked to aging and inflammation, which may worsen heart attacks and heart disease.

Contribution

The study identifies novel senescence-related genes in epicardial adipose tissue that drive immune infiltration and CAD progression.

Findings

Senescence-related genes like STAT3 and LRP1 are highly expressed in severe CAD and hypoxic adipocytes.

Knockdown of these hub genes reduces SASPs like IL1α and IL6 in hypoxic adipocytes.

The joint ROC of 5 genes reached 1, indicating strong predictive power for CAD progression.

Abstract

After coronary artery disease (CAD)-related myocardial injury, reactivation of the epicardium results in cardiac remodeling via paracrine secretion. However, the senescence-related genomic signature that reflects epicardial adipose tissue (EAT) and immune infiltration is not well understood.

Adipocyte-related differentially expressed genes (DEGs) were identified in EAT and subcutaneous adipose tissue (SAT) from patients with and without CAD. Immune cells and senescence-related DEGs in EATs were identified. A protein-protein interaction network was used to determine the hub genes. To validate these genes, a Gene Expression Omnibus (GEO) dataset investigation, single cell sequencing analysis and the validation of human sub-epicardial adipose and blood samples were performed. To investigate the mechanism, 3T3-L1 cells were used and differentiated to adipocytes and the hub genes were knocked-down and SASPs were determined.

A Venn diagram was used to obtain 82 senescence-related DEGs, and the top 15-degree hub genes were explored. After validating using the GEO datasets and human sub-epicardial adipose samples, STAT3, SERPINE1, CDKN2A, DLG4, PTGS2, MDM2, LRP1, IRS2, PRKCD, CCND2, and CISH were found to be significantly expressed in the group with severe CAD. The hub genes, including STAT3, MDM2, LRP1, IRS2, PRKCD, CCND2, and CISH, were validated to be highly expressed in adipocytes in ischemic cardiomyopathy patients with end-stage heart failure. STAT3, LRP1, PRKCD, CCND2, and CISH were highly expressed in adipocytes under hypoxia. STAT3, LRP1, PRKCD, CCND2, and CISH were knocked-down in 3T3-L1 cell lines. SASPs, including IL1α, IL1β, and TNFα, decreased in hypoxic adipocytes after 5 hub genes knockdown. IL6 decreased in hypoxic adipocytes after STAT3, LRP1, and CISH knockdown, while IL6 increased in hypoxic adipocytes after CCND2 knockdown. The joint ROC of all 5 genes expression was 1.

These screened SASP hub genes, including STAT3, LRP1, PRKCD, CCND2, and CISH, may affect cell senescence after hypoxia, thus inducing CAD progression.

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