Enhanced Plasma Levels of LIGHT in Unstable Angina

Abstract

Background-Numerous studies have demonstrated the ability of oxidized LDL [(ox)LDL] to promote an inflammatory response in macrophages. Several inflammatory mediators have been reported to increase after oxLDL stimulation of such cells, but their relative importance is still unknown. In the present study, we used microarrays to identify genes in THP-1 macrophages that were upregulated by oxLDL. Methods and Results-Our main findings were as follows. In a microarray screening experiment, we identified LIGHT, a ligand in the tumor necrosis factor superfamily, as one of the genes that were markedly upregulated in oxLDL-stimulated THP-1 macrophages. We showed significantly raised plasma levels of LIGHT in patients with stable angina (nϭ40) and particularly in those with unstable angina (nϭ40) compared with healthy controls (nϭ20), which underscores the clinical relevance of the in vitro finding. We also showed that LIGHT enhanced lipid accumulation in oxLDL-stimulated THP-1 macrophages, possibly through upregulation of class A scavenger receptor (SR-A). This increased lipid accumulation was accompanied by enhanced expression of tissue factor and plasminogen activator inhibitor-1, as well as enhanced thrombin formation, transforming macrophages into a prothrombotic phenotype. The LIGHT-mediated increase in SR-A, tissue factor, and plasminogen activator inhibitor-1 was also seen in human monocyte-derived macrophages. Finally, the LIGHT-mediated enhancement of SR-A and TF expression appears to involve nuclear factor-B activation. Conclusions-These findings suggest that LIGHT could serve as a molecular link between lipid metabolism, inflammation, and thrombus formation, which are all features of atherosclerotic plaques.

Increased expression of LIGHT/TNFSF14 and its receptors in experimental and clinical heart failure☆

“…Independent of the mechanisms, our findings of a LIGHT-mediated IL-6 response in PBMC and endothelial cells, may further support a role for LIGHT in the progression of HF. LIGHT has previously been shown to promote atherogenesis [12,13]. Our findings in the present study suggest that this TNF superfamily ligand could also be involved in the progression of chronic HF, independent of the presence of CAD.…”

“…However, while several studies have examined the pathogenic role of LIGHT in a variety of animal models [10], there are few reports on the role of this cytokine in human disorders. Recently, enhanced LIGHT expression was found in human atherosclerotic disorders, potentially promoting lipid accumulation, matrix degradation, and thrombus formation [12,13]. Herein we show increased expression of LIGHT and its receptors in human HF both within the failing myocardium (i.e., HVEM), and in circulating T-cells (i.e., LIGHT) and monocytes (i.e., HVEM and LTβR).…”

“…The study was approved by the local ethics committee. Blood samples for the study (plateletpoor EDTA plasma) were collected and stored as previously described [12].…”

“…Studies in animal models indicate that LIGHT may be crucial for the development of various autoimmune disorders (e.g., inflammatory bowel disease and rheumatoid arthritis) through effects on T-cells and T-cell homing into inflamed tissues [10,11]. This cytokine has also been suggested to promote atherogenesis at least partly by inducing matrix metalloproteinase (MMP) activity in macrophages and inflammation in endothelial cells [12,13], and very recently LIGHT was shown to be involved in regulation of lipid homeostasis [14]. Based on these properties, we hypothesized that LIGHT could also be involved in the progression of chronic HF.…”

LIGHT is associated with hypertriglyceridemia in obese subjects and increased cytokine secretion from cultured human adipocytes

“…20 This cytokine has also been suggested to promote atherogenesis by inducing matrix metalloproteinase activity and inflammation in macrophages. 21,22 Recently, LIGHT signalling pathway has been related with the progression of chronic heart failure involving IL-6-related mechanisms. 23 Tumor necrosis factor is also described as a molecule that causes hypertriglyceridemia and wasting of muscle and fat tissue.…”