Iron modulates phagocyte-endothelial cell interactions: Implications for atherosclerosis

Abstract

Atherosclerotic heart disease has claimed the lives of millions of people each year in the Western world, and rapidly increases in prevalence in many other places. The disease results from cholesterolemia, coupled with a chronic inflammatory condition of the vascular wall that lead to vessel occlusion and various clinical manifestations.In 1981, Sullivan suggested possible benefits of iron depletion against coronary artery disease, from the observations where men and menopausal women were more prone to develop this disease. Following Sullivan’s proposal, basic and clinical data have begun to provide explanations for a link between iron and atherosclerosis (Chapter 1). This thesis has aimed to investigate the role of iron in the inflammatory events crucial in atherogenesis, especially in the course of phagocyte-endothelial cell interactions.In vitro studies described in this thesis reveals an immunomodulatory function of iron in inflammation. Chapter 2 and Chapter 3 show that NTBI promotes accumulation of intracellular labile iron and production of oxygen-derived free radicals, leading to cell activation. Activation of endothelial cells is a well-characterized phenotype that leads to endothelial dysfunction in vivo, which not only will initiate the development of atherosclerosis, but also plays a role at a critical late step of thrombosis, promoting vessel occlusion and acute cardiovascular events. In combination with chronic infections iron enhances infection-induced endothelial activation (Chapter 4), implying that in the presence of other stressors, iron may contribute significantly in aggravating atherogenesis. In addition, in Chapter 6, the drawbacks of EDTA chelation therapy particularly in inducing endothelial activation are described. The use of this alternative therapy for atherosclerosis therefore needs to be critically reconsidered, especially in regards to its effectiveness and safety. Furthermore, iron also promotes monocyte (Chapter 2 and Chapter 5) and neutrophil (Chapter 7) activation. An increased number of phagocyte infiltrates may thus complicate the progression of atherosclerotic vascular diseases. The infiltration of monocytes also play a role in neuroinflammation, stimulating the development of neurodegenerative diseases. Finally, Chapter 8 demonstrates the involvement of iron in enhancing the rate and the production of oxidised LDL cholesterol, especially through interactions with phagocyte-derived oxygen metabolites. Based on the findings in this thesis, iron depletion and iron chelation could be beneficial for such unfavourable conditions generated by iron. The identified modifying role of iron in inflammation described in this study (Chapter 9) offers an additional strategy for prevention and therapy of inflammatory diseases, like atherosclerotic vascular diseases and neurodegenerative diseases.