Lipocalin-2, S100A8/A9, and cystatin C: Potential predictive biomarkers of cardiovascular complications in COVID-19

Abstract

Severe coronavirus (SARS-COV-2) infection often leads to systemic inflammation accompanied by cardiovascular complications including venous thromboembolism (VTE). However, it is largely undefined if inflammatory markers such as lipocalin-2 (LNC2), calprotectin (S100A8/A9), and cystatin C (CST3), previously linked with VTE, play roles in cardiovascular complications and advancement of COVID-19 severity. To investigate the same, hospitalized moderate and severe (presented pneumonia and required intensive care) COVID-19 patients were recruited. The levels of plasma LNC2, S100A8/A9, CST3, myoglobin, and cardiac Troponin I (cTnI) were assessed through enzyme-linked immunosorbent assay (ELISA). The investigation revealed a significantly upregulated level of plasma LNC2 at the moderate stage of SARS-CoV-2 infection. In contrast, the levels of S100A8/A9 and CST3 in moderate patients were comparable to healthy controls; however, a profound induction was observed only in severe COVID-19 patients. The tissue injury marker myoglobin was unchanged in moderate patients; however, a significantly elevated level was observed in the critically ill COVID-19 patients. In contrast, cTnI level was unchanged both in moderate and severe patients. Analysis revealed a positive correlation between the levels of S100A8/A9 and CST3 with myoglobin in COVID-19. In silico analysis predicted interactions of S100A8/A9 with toll-like receptor 4 (TLR-4), MyD88 LY96, and LCN2 with several other inflammatory mediators including MMP2, MMP9, TIMP1, and interleukins (IL-6, IL-17A, and IL-10). In summary, early induction of LCN2 likely plays a role in advancing the COVID-19 severity. A positive correlation of S100A8/A9 and CST3 with myoglobin suggests that these proteins may serve as predictive biomarkers for thromboembolism and tissue injury in COVID-19.

TFPI and FXIII negatively and S100A8/A9 and Cystatin C positively correlate with D-dimer in COVID-19

“…Since a significant positive correlation between CST3 and D-dimer was also observed (Figure 4(B)), S100A8/ A9 likely induces thromboembolism and tissue injury in COVID-19 partly through CST3 as we recently reported positive correlations of S100A8/A9 and CST3 with myoglobin. 14 Consistently, the positive correlation between myoglobin and D-dimer (Figure 4(C)) further attests to the role of thromboembolism in SARS-CoV-2 mediated tissue injury.…”

“…The coagulation, fibrinolysis, tissue injury markers, and inflammatory markers were assessed and reported by us recently. 13,14 Briefly, the coagulation dysfunction, endothelial cell activation and fibrinolysis markers including fibrinogen, FXIII, P-selectin, soluble CD40 ligand (sCD40 L), tissue plasminogen activator (tPA), plasminogen activator inhibitor-I (PAI-I), and D-Dimer were assessed in plasma employing flow cytometry-based LegendPlex kits (BioLegend #740906, #740761) following the manual instructions. The level of tissue factor pathway inhibitor (TFPI) in plasma was assessed using an ELISA kit (Abcam #ab274392) following the manufacturer’s instruction.…”

SARS-CoV-2 infection- induced growth factors play differential roles in COVID-19 pathogenesis

“…Several GFs play important roles in maintaining endothelial activity and vascular integrity and an imbalance in GFs may induce VTE [7] . We recently reported the significantly elevated levels of D-dimer [29] and tissue injury marker myoglobin [6] , particularly in the ICU group of these patients. Therefore, next, we investigated the potential roles of selected GFs in thromboembolism and tissue injury or repair through their correlation with D-dimer and myoglobin in COVID-19 patients.…”

“…The age range of moderate patients was between 32 and 67 years (median age of 48 years) and between 38 and 69 years (median age of 57 years) for severe patients. The detailed clinical laboratory parameters and medications of these patients were reported recently [6] , [29] . Briefly, there was an induction of inflammatory reaction in these patients which was attested by an elevated level of plasma c-reactive protein (CRP), a higher number of white blood cells (WBCs) including absolute lymphocyte counts (ALC), particularly in severe COVID-19 cases.…”

“…They regulate several pathophysiological conditions including tissue injury and repair through binding to specific receptors on the cell via paracrine and/or autocrine mechanisms [3] , [4] . SARS-CoV-2-induced cytokines and GFs mediate coagulation dysfunction and tissue injury, which contribute to the clinical severity of COVID-19 [5] , [6] . Changes in plasma cytokines and GFs level increases the risk of venous thromboembolism (VTE) [7] , [8] , characterized by elevated D-dimer and, a major cause of tissue injury in the severe COVID-19.…”