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ITGB2 is a Central Hub-Gene Associated with Early Fibro-Atheroma Development in A Swine Model of Atherosclerosis

ABSTRACT: Atherosclerosis is an inflammatory-driven disease involving complex mechanisms. Our study investigated the transcriptomic profile of swine abdominal aortic tissues with atherosclerotic lesions, identified pathways and biological processes that were enriched in DEGs, determined a set of hub genes central to atherosclerosis pathophysiology that may serve as potential therapeutic targets, and established a positive expression correlation between the top hub gene and its interconnecting genes upon in vitro manipulation. Our data showed that WMS FH exhibits immune and inflammation-related pathways. RNA-Seq result demonstrated distinct expression patterns between abdominal aortic tissue with atherosclerotic lesions (WMS FH) and lesion-free tissues (WMS normal) both at the gene and isoform levels. Ten hub genes were identified, including ITGB2, C1QA, LCP2, SPI1, CSF1R, CSF2RB, C5AR1, CTSS, MPEG1, C1QC. Moreover, manipulating the top-ranked gene (ITGB2) expression in porcine endothelial cells affected the expression of interconnecting genes.

ORGANISM(S): Sus scrofa

PROVIDER: GSE199592 | GEO | 2023/11/24

REPOSITORIES: GEO

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Project description:Background: Biological-sex differences play a vital role in cardiovascular diseases, including atherosclerosis. The endothelium is a critical contributor to cardiovascular pathologies since endothelial cells (EC) regulate vascular tone, redox balance, and inflammatory reactions. Although EC activation and dysfunction play an essential role in the early and late stages of atherosclerosis development, little is known about sex-dependent differences in EC. Methods: We used aortic EC that was isolated from 13-week-old female and male mice as well as EC-lineage tracing (Cdh5-CreERT2 Rosa-YFP) atherosclerotic Apoe‒/‒ mice to investigate the biological sexual dimorphism of the EC functions in vitro and in vivo. RNA sequencing (RNAseq) analyses were performed on male and female mouse aortic EC and human lung EC. Results: In vitro, female mouse aortic EC (F_MAEC) showed more apoptosis and higher cellular ROS levels, lower mitochondrial membrane potential (ΔΨm), and lower levels of mitochondrial transcription factor A (TFAM) than male aortic EC (M_MAEC). Additionally, F_MAEC had decreased angiogenic potential (tube formation, cell viability, and proliferation) compared to M_MAEC. In vivo, female mice had significantly higher lipid accumulation within the aortas, less efficient outward vessel remodeling, and lower endothelial-mediated vasorelaxation than males. Using the EC-lineage tracing approach, we found that female lesions had significantly lower rates of intraplaque neovascularization and Endothelial-to-Mesenchymal (EndoMT) transition within advanced atherosclerotic lesions but higher incidents of missing EC lumen coverage and higher levels of oxidative products and apoptosis. RNAseq analyses revealed that both mouse and human female EC had higher expression of genes associated with inflammation and apoptosis and lower expression of genes related to angiogenesis and oxidative phosphorylation than male EC. Conclusions: Our study delineates critical sex-specific differences in EC relevant to pro-inflammatory, pro-oxidant, and angiogenic characteristics, which are entirely consistent with a vulnerable phenotype in females. Our results provide a biologic basis for sex-specific pro-atherosclerotic mechanisms.

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ITGB2 is a Central Hub-Gene Associated with Early Fibro-Atheroma Development in A Swine Model of Atherosclerosis

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