Abstract
ObjectivesCurrently, 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.MethodologyWeighted 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.ResultsHIF-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. Proteomic analysis showed that IL18/IL18R1 promote NF-κB entry into the nucleus, and activated the HIF-1 signaling pathway. Macrophage-derived IL18 promoted the M1 polarization of macrophages and the syntactic phenotype transformation of VSMCs. MAP2K1 mediates the functional regulation of HIF-1 signaling pathway in various cell types. Epigenetic changes in PBMC after COVID-19 infection are characterized by activation of the type I interferon pathway. MEK inhibitors are the promising compounds for the treatment of HIF-1 overactivation.ConclusionsThe IL18/IL18R1/HIF1A axis is expected to be an therapeutic target for cardiovascular protection after SARS-CoV-2 infection. MEK inhibitors may be an choice for cardiovascular protection after SARS-COV-2 infection
Highlights
COVID-19 is a global respiratory epidemic caused by SARS-CoV2, currently infects at least 68 million people, and the number of cases is rising with the emergence of mutated strains such as Delta [1] and Omicron [2]
We found that MAP2K1 plays a key role and that MEK inhibitors can be used as treatment options for cardiovascular sequelae after COVID-19
The HIF-1 Signaling Pathway Is a Key Pathway for SARS-CoV-2 Infection, Aneurysms and Atherosclerosis In GSE156754, human induced pluripotent stem cells and iPSCs-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells were infected with SARS-CoV-2 and compared with uninfected cells
Summary
COVID-19 is a global respiratory epidemic caused by SARS-CoV2, currently infects at least 68 million people, and the number of cases is rising with the emergence of mutated strains such as Delta [1] and Omicron [2]. Clinical studies have shown that the severity of COVID-19 is positively correlated with levels of inflammatory factors [6, 7], which can cause ARDS, diffuse intravascular coagulation and multiple organ failure. Induction of these cytokines is mediated by [8]: (I) the angiotensin II/AT1R pathway; (ii) ACE2 signaling pathway; (iii) Innate immune signaling pathways, including PRRs such as TLRs, RIG-1, and MDA5 signaling pathways, nucleotide binding oligomer domains (NOD), Leucine-rich repeat domain (LRR), and Pyrin domain-containing protein 3 (NLRP3) inflammasome. The HIF-1 signaling pathway participate in the process of SARS-CoV-2 infection [9] and aggravate the inflammatory response to COVID-19 [10]
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