ABSTRACT
Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1ß and TNF-α, two cytokines elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis, and reduced angiogenesis). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.
Subject(s)
COVID-19 , Human Umbilical Vein Endothelial Cells , Kruppel-Like Transcription Factors/biosynthesis , SARS-CoV-2 , COVID-19/genetics , COVID-19/metabolism , COVID-19/pathology , COVID-19/prevention & control , Cytokines/biosynthesis , Cytokines/genetics , Gene Expression Regulation , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Human Umbilical Vein Endothelial Cells/virology , Humans , Intercellular Adhesion Molecule-1/biosynthesis , Intercellular Adhesion Molecule-1/genetics , Kruppel-Like Transcription Factors/genetics , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Vascular Cell Adhesion Molecule-1/biosynthesis , Vascular Cell Adhesion Molecule-1/geneticsABSTRACT
AIMS/INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic urged authorities to impose rigorous quarantines and brought considerable changes to people's lifestyles. The impact of these changes on glycemic control has remained unclear, especially the long-term effect. We aimed to investigate the impact of COVID-19 lockdown on glycemic control in children and adolescents with type 1 diabetes. MATERIALS AND METHODS: This observational study enrolled children with type 1 diabetes using continuous glucose monitoring. Continuous glucose monitoring data were extracted from the cloud-based platform before, during and after lockdown. Demographics and lifestyle change-related information were collected from the database or questionnaires. We compared these data before, during and after lockdown. RESULTS: A total of 43 children with type 1 diabetes were recruited (20 girls; mean age 7.45 years; median diabetes duration 1.05 years). We collected 41,784 h of continuous glucose monitoring data. Although time in range (3.9-10.0 mmol/L) was similar before, during and after lockdown, the median time below range <3.9 mmol/L decreased from 3.70% (interquartile range [IQR] 2.25-9.53%) before lockdown to 2.91% (IQR 1.43-5.95%) during lockdown, but reversed to 4.95% (IQR 2.11-9.42%) after lockdown (P = 0.004). Time below range <3.0 mmol/L was 0.59% (IQR 0.14-2.21%), 0.38% (IQR 0.05-1.35%) and 0.82% (IQR 0.22-1.69%), respectively (P = 0.008). The amelioration of hypoglycemia during lockdown was more prominent among those who had less time spent <3.9 mmol/L at baseline. During lockdown, individuals reduced their physical activity, received longer sleep duration and spent more time on diabetes management. In addition, they attended outpatient clinics less and turned to telemedicine more frequently. CONCLUSION: Glycemic control did not deteriorate in children and teenagers with type 1 diabetes around the COVID-19 pandemic. Hypoglycemia declined during lockdown, but reversed after lockdown, and the changes related to lifestyle might not provide a long-term effect.