Cardiovascular Risk After SARS-CoV-2 Infection Is Mediated by IL18/IL18R1/HIF-1 Signaling Pathway Axis

作者：Liwei Zhang, Mingxing Li, Zhiwei Wang, Peng Sun, Shunbo Wei, Cong Zhang, Haoliang Wu, Hualong Bai · 发表于：Frontiers in Immunology · 年份：2022 · DOI：10.3389/fimmu.2021.780804 · 被引用次数：36 · 研究领域：Inflammasome and immune disorders、interferon and immune responses、COVID-19 Clinical Research Studies

Objectives: Currently, cardiovascular risk associated with COVID-19 has been brought to people's attention, but the mechanism is not clear. The aim of this study is to elucidate the mechanisms based on multiple omics data. Methodology: Weighted gene co-expression network analysis (WGCNA) was used to identify key pathways. Combination analysis with aneurysm and atherosclerosis related pathways, hypoxia induced factor-1 (HIF-1) signaling were identified as key pathways of the increased cardiovascular risk associated with COVID-19. ScMLnet algorithm based on scRNA-seq was used to explore the regulation of HIF-1 pathway by intercellular communication. Proteomic analysis was used to detect the regulatory mechanisms between IL18 and HIF-1 signaling pathway. Pseudo time locus analysis was used to study the regulation of HIF1 signaling pathway in macrophages and vascular smooth muscle cells (VSMC) phenotypic transformation. The Virtual Inference of protein-activity by Enriched Regulon (VIPER) analysis was used to study the activity of regulatory proteins. Epigenetic analysis based on methylation revealed epigenetic changes in PBMC after SARS-CoV-2 infection. Potential therapeutic compounds were explored by using Cmap algorithm. Results: HIF-1 signaling pathway is a common key pathway for aneurysms, atherosclerosis and SARS-CoV-2 infection. Intercellular communication analysis showed that macrophage-derived interleukin-18 (IL-18) activates the HIF-1 signaling pathway through IL18R1. P...