The CD40-CD40L system in cardiovascular disease.
ABSTRACT The CD40-CD40L system is a pathway which is associated with both prothrombotic and proinflammatory effects. CD40 and its ligand were first discovered on the surface of activated T cells, but its presence on B cells, antigen-presenting cells, mast cells, and finally platelets, is evident. The soluble form of CD40L (sCD40L) is derived mainly from activated platelets and contributes to the pathophysiology of atherosclerosis and atherothrombosis. Indeed, sCD40L has autocrine, paracrine, and endocrine activities, and it enhances platelet activation, aggregation, and platelet-leucocyte conjugation that may lead to atherothrombosis. It has even been suggested that sCD40L may play a pathogenic role in triggering acute coronary syndromes. Conversely, blockade of this pathway with anti-CD40L antibodies may prevent or delay the progression of atherosclerosis. Concentrations of sCD40L also predict risk of future cardiovascular disease in healthy women and clinical outcomes in patients with acute coronary syndromes. However, there are controversial and uncertain points over the application of this biomarker to clinical cardiology. In this review, we provide an overview of potential implications of CD40-CD40L signalling and sCD40L as a biomarker in patients with atherosclerotic vascular diseases.
- SourceAvailable from: Mariana S Parahuleva[Show abstract] [Hide abstract]
ABSTRACT: Objective: Atherosclerosis, as an inflammatory disease, is characterized by pathologically altered levels of cytokines. We investigated whether smoking and/or oral contraceptives (OCs) affect the CD40/CD40L plasma levels and expression in young females without other risk factors for atherosclerosis. Patients and Methods: A case-control single-center design was used. Expression levels of CD40/CD40L were analyzed in healthy non-pregnant, pre-menopausal, non-smoking women who did not take OCs (n = 49), women who currently smoke and take OCs (n = 40), and women who are only smokers (n = 40) or currently take OCs (n = 42). Results: In OC users, there was a significant increase in CD40 mRNA expression in circulating monocytes as compared with smokers and control group. However, there were no significant differences in CD40 mRNA expression in monocytes between smokers and non-smokers. Interestingly, CD40 mRNA expression in women taking OCs and currently smoking was significantly decreased compared to only OC users (p < 0.001). With regard to plasma CD40 levels there were significant differences between OC-users and control group. However, contrary to our expectations, there were no significant differences in expression levels of CD40L between four groups. In vitro experiments demonstrated enhanced CD40 mRNA and surface expression in human monocyte-derived macrophages stimulated with estrogens. Furthermore, nicotine pretreatment led to a suppression of estrogens stimulated CD40 induction. Conclusions: In young healthy females without additional risk factors for atherosclerosis, OCs, but not smoking, are associated with dramatic changes in CD40 gene and plasma levels. These findings may be providing an important link between OCs and enhancement of pro-inflammatory and atherothrombotic conditions in healthy women.Thrombosis Research 12/2014; 135(2). DOI:10.1016/j.thromres.2014.11.035 · 2.43 Impact Factor
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ABSTRACT: Atherosclerotic cardiovascular disease is the leading cause of death in many developed countries. It is characterized by complex endocrine, paracrine and juxtacrine interactions between immune and vascular cells, as well as several tissues and organs. Oxidative stress and inflammation have an important role in the promotion of atherosclerotic cardiovascular disease. Considering the complicated mechanisms and signals involved in atherosclerosis, research is focused on blood-based biomarkers, gene-based markers, metabolomics and other potentially interesting approaches for biomarker discovery. These biomarkers can be introduced as routine diagnostic tests if they prove to be cost-effective and to predict future cardiovascular events. Given the overlap of circulating inflammatory and oxidative stress biomarkers in atherosclerosis and rheumatic diseases, we aim to overview their potential to screen cardiovascular risk and also to predict the evolution of associated rheumatic diseases.Current pharmaceutical design 04/2013; · 3.29 Impact Factor
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