Immunopathogenic mechanisms of Coronary Artery Disease and plaque destabilization
Year: 2008
Type: dissertation
Abstract: Inflammation seems to play a role in both the chronic atherosclerotic process as well as in plaque destabilization, leading to the development of acute coronary syndromes (ACS). The aim of this study was to further investigate the immunopathogenic mechanisms in patients with coronary artery disease (CAD), primarily focusing on i) the pathogenic role of chemokines, ii) platelet-mediated inflammation, and iii) the pathogenic role of activin A as a potential “new” anti-inflammatory mediator in this process. We found that platelets upon activation released the inflammatory cytokine LIGHT, a member of the TNF superfamiliy, and that platelet-derived LIGHT could promote endothelial cell activation, potentially contributing to vascular inflammation in atherosclerotic disorders. The traditionally platelet-derived chemokine NAP-2 was also produced by peripheral mononuclear cells (PBMC), and we found that NAP-2 has the potential to induce an inflammatory response within the atherosclerotic plaque involving interaction between platelets, leukocytes and endothelial cells. By its ability to promote leukocyte activation as well as expression of chemokines and adhesion molecules within the vessel wall, such a NAP-2-driven inflammation could ultimately lead to plaque rupture and ACS. CAD patients had raised levels of the CXC chemokine CXCL16, with significantly down-regulatory effects of statins. Our in vitro experiments, showing potential inflammatory and matrix degrading properties of CXCL16, indicate that soluble CXCL16 is not only a marker, but also a mediator of inflammation with particularly enhancing effects in CAD patients. We also showed abnormal regulation of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in atherosclerosis with particularly disturbed expression in unstable and advanced clinical and experimental disease. By recruiting T cells and macrophages to the atherosclerotic lesions, by promoting inflammatory responses in T cells, and by inducing a matrix degrading, pro-thrombotic, and inflammatory phenotype in macrophages, these chemokines could contribute to atherogenesis and plaque destabilization. In contrast, activin A, which was found to be up-regulated in CAD patients, was shown to display anti-inflammatory properties on mononuclear cells, in particular in patients with unstable disease. Our findings illustrate the complex regulation of the inflammatory responses during atherogenesis and plaque destabilization. Further studies on these aspects could potentially lead to new treatment modalities in these disorders.
Author: Camilla Smith
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2410676734