Oxidized low-density lipoproteins induce tissue factor expression in T-lymphocytes via activation of lectin-like oxidized low-density lipoprotein receptor-1. Issue 6 (27th August 2019)

• Record Type: Journal Article
• Authors: Cimmino, Giovanni; Cirillo, Plinio; Conte, Stefano; Pellegrino, Grazia; Barra, Giusi; Maresca, Lucio; Morello, Andrea; Calì, Gaetano; Loffredo, Francesco; De Palma, Raffaele; Arena, Giulia; Sawamura, Tatsuya; Ambrosio, Giuseppe; Golino, Paolo
• Is Part Of: Cardiovascular research. Volume 116:Issue 6(2020)
• Page Start: 1125
• Page End: 1135
• Publication Date: 2019-08-27
• Subjects: Lipoproteins -- Atherosclerosis -- Inflammation -- T-lymphocyte -- Tissue factor; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvz230
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: T-lymphocytes plays an important role in the pathophysiology of acute coronary syndromes. T-cell activation in vitro by pro-inflammatory cytokines may lead to functional tissue factor (TF) expression, indicating a possible contribution of immunity to thrombosis. Oxidized low-density lipoproteins (oxLDLs) are found abundantly in atherosclerotic plaques. We aimed at evaluating the effects of oxLDLs on TF expression in T cells and the role of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Methods and results: CD3 + cells were isolated from healthy volunteers. Gene, protein, and surface expression of TF, as well as of LOX-1, were assessed at different time-points after oxLDL stimulation. To determine whether oxLDL-induced TF was LOX-1 dependent, T cells were pre-incubated with an LOX-1 inhibiting peptide (L-RBP) or with an anti-LOX-1 blocking antibody. To exclude that TF expression was mediated by reactive oxygen species (ROS) generation, oxLDL-stimulated T cells were pre-incubated with superoxide dismutase + catalase or with 4-Hydroxy-2, 2, 6, 6-tetramethylpiperidine-1-oxyl (Tempol), an intracellular free radical scavenger. Finally, to determine if the observed findings in vitro may have a biological relevance, the presence of CD3 + /TF + /LOX-1 + cells was evaluated by immunofluorescence in human carotid atherosclerotic lesions. oxLDLs induced functionally active TF expression in T cells in a dose- and time-dependent manner, independently on ROS generation. No effect was observed in native LDL-treated T cells. LOX-1 expression was also induced by oxLDLs in a time- and dose-dependent manner. Pre-incubation with L-RBP or anti-LOX-1 antibody almost completely inhibited oxLDL-mediated TF expression. Interestingly, human carotid plaques showed significant infiltration of CD3 + cells (mainly CD8 + cells), some of which were positive for both TF and LOX-1. Conclusion: oxLDLs induce functional TF expression in T-lymphocytes in vitro via interaction of oxLDLs with LOX-1. Human carotid atherosclerotic plaques contain CD3 + /CD8 + cells that express both TF and LOX-1, indicating that also in patients these mechanisms may play an important role. Graphical Abstract: