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

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

UPLC-MS/MS Profiling, Antioxidant, α-Glucosidase Inhibitory, Cholinesterase Inhibitory, and Cardiovascular Protection Potentials of Jialing 20 (Morus multicaulis Perr.) Mulberry Branch Extract

As a by-product in the sericulture industry, mulberry branches are not currently utilized effectively. Jialing 20 is an artificial triploids mulberry that widely cultivated in southwest China. In this study, the chemical composition of the Jialing 20 mulberry branch extract (MBE) was first analyzed by UPLC-MS/MS, and 42 components, including alkaloids, flavonoids, and coumarins, were obtained. Then, the antioxidant activities, hypoglycemic effect, Alzheimer’s disease inhibition, and cardiovascular protection of MBE were also evaluated in vitro. The IC50 values for the scavenging DPPH and ABTS radicals were, respectively, 31.23 ± 0.57 μg/mL and 8.88 ± 0.36 μg/mL (IC50 values of positive Vc were, respectively, 4.41 ± 0.19 μg/mL and 8.79 ± 0.41 μg/mL). The IC50 value for inhibiting α-glucosidase was 1.90 ± 0.05 μg/mL (IC50 value of positive acarbose was 0.03 μg/mL). The IC50 values for inhibiting acetylcholinesterase and butyrylcholinesterase were, respectively, 179.47 ± 0.38 μg/mL and 101.82 ± 3.37 μg/mL (IC50 values of positive berberine were, respectively, 1.27 ± 0.03 μg/mL and 57.41 ± 0.21 μg/mL). MBE (10 μg/mL and 40 μg/mL) significantly increased the survival rate of oxidized low-density lipoprotein- (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) and significantly decreased the intracellular reactive oxygen species. These results suggest that the extracts of Jialing 20 mulberry branches could be used as a functional food additive.