ABSTRACT
Proinflammatory agonists provoke the expression of cell surface adhesion molecules on endothelium in order to facilitate leukocyte infiltration into tissues. Rigorous control over this process is important to prevent unwanted inflammation and organ damage. Protein L-isoaspartyl O-methyltransferase (PIMT) converts isoaspartyl residues to conventional methylated forms in cells undergoing stress-induced protein damage. The purpose of this study was to determine the role of PIMT in vascular homeostasis. PIMT is abundantly expressed in mouse lung endothelium and PIMT deficiency in mice exacerbated pulmonary inflammation and vascular leakage to LPS(lipopolysaccharide). Furthermore, we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6) and its ability to methylate asparagine residues in the coiled-coil domain. This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation and subsequent expression of endothelial adhesion molecules. Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation, causing effects on protein stability that ultimately translated into reduced EC(endothelial cell)-leukocyte interactions. Our study has identified PIMT as a novel and potent suppressor of endothelial activation. Taken together, these findings suggest that therapeutic targeting of PIMT may be effective in limiting organ injury in inflammatory vascular diseases.
Subject(s)
Lipopolysaccharides , Protein D-Aspartate-L-Isoaspartate Methyltransferase , TNF Receptor-Associated Factor 6 , Animals , Mice , Endothelial Cells/metabolism , Endothelium/metabolism , Lipopolysaccharides/metabolism , Signal Transduction , TNF Receptor-Associated Factor 6/genetics , TNF Receptor-Associated Factor 6/metabolism , Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics , Protein D-Aspartate-L-Isoaspartate Methyltransferase/metabolismABSTRACT
Objective: Cardiac injury is detected in numerous patients with coronavirus disease 2019 (COVID-19) and has been demonstrated to be closely related to poor outcomes. However, an optimal cardiac biomarker for predicting COVID-19 prognosis has not been identified. Methods: The PubMed, Web of Science, and Embase databases were searched for published articles between December 1, 2019 and September 8, 2021. Eligible studies that examined the anomalies of different cardiac biomarkers in patients with COVID-19 were included. The prevalence and odds ratios (ORs) were extracted. Summary estimates and the corresponding 95% confidence intervals (95% CIs) were obtained through meta-analyses. Results: A total of 63 studies, with 64,319 patients with COVID-19, were enrolled in this meta-analysis. The prevalence of elevated cardiac troponin I (cTnI) and myoglobin (Mb) in the general population with COVID-19 was 22.9 (19-27%) and 13.5% (10.6-16.4%), respectively. However, the presence of elevated Mb was more common than elevated cTnI in patients with severe COVID-19 [37.7 (23.3-52.1%) vs.30.7% (24.7-37.1%)]. Moreover, compared with cTnI, the elevation of Mb also demonstrated tendency of higher correlation with case-severity rate (Mb, r = 13.9 vs. cTnI, r = 3.93) and case-fatality rate (Mb, r = 15.42 vs. cTnI, r = 3.04). Notably, elevated Mb level was also associated with higher odds of severe illness [Mb, OR = 13.75 (10.2-18.54) vs. cTnI, OR = 7.06 (3.94-12.65)] and mortality [Mb, OR = 13.49 (9.3-19.58) vs. cTnI, OR = 7.75 (4.4-13.66)] than cTnI. Conclusions: Patients with COVID-19 and elevated Mb levels are at significantly higher risk of severe disease and mortality. Elevation of Mb may serve as a marker for predicting COVID-19-related adverse outcomes. Prospero Registration Number: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020175133, CRD42020175133.