Statins and the vascular endothelial inflammatory response - PubMed (original) (raw)
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Statins and the vascular endothelial inflammatory response
John Greenwood et al. Trends Immunol. 2007 Feb.
Abstract
Statins reduce cholesterol synthesis and are widely used for the treatment of hyperlipidaemia and ischaemic heart disease. Besides their cholesterol-lowering effects, statins also possess broad immunomodulatory and anti-inflammatory properties. Vascular endothelial cells have a crucial role in the pathogenesis of inflammatory disease, and, alongside leukocytes and antigen-presenting cells, represent a key cellular target for statin therapy. Recent studies investigating how these drugs modify endothelial cell function demonstrate that the therapeutic effect of statins can be attributed, in part, to their action on the endothelium. Accordingly, statins attenuate endothelial MHC class II expression, increase endothelial nitric oxide synthase and fibrinolytic activity, decrease leukocyte adhesion and transmigration, and enhance resistance to local injurious stimuli. Many of these effects are brought about by the modulation of small GTPase function and the downregulation of proinflammatory gene expression.
Figures
Figure 1. Effects of statins on the pro-inflammatory vascular endothelium
During inflammation the endothelial cell is activated leading to the induction and upregulation of numerous signaling pathways that promote the inflammatory event (illustrated by red arrows). Statins downregulate a number of these key pathways including those responsible for pro-inflammatory gene induction, support of leukocyte migration and increased cell junction permeability. The negative effect of statins on proinflammatory gene regulation results in reduced expression of MHC class II, CD40, adhesion molecules, chemokines, cytokines, MMPs and chemokine receptors. In addition, statins inhibit pathways that downregulate anti-inflammatory responses which results in increased eNOS mRNA stability and NO production which has anti-inflammatory effects. Red arrows represent those pathways that are blocked by statins primarily through their action on small GTPase prenylation and blue boxes describe the outcome of statin treatment.
Figure 2. Cytoprotective effects of statins on vascular endothelium
Defined and potential signalling pathways through which statins may exert vasculoprotective effects on the pro-inflammatory vascular endothelium are shown. Statins induce cytoprotective genes, protect against vascular injury and reverse endothelial cell dysfunction. Activation of PI3K/Akt and increased NO biosynthesis prevent apoptosis, increase vasodilatation and reduce leukocyte and platelet adhesion. Through inhibition of Rac-1-mediated NAD(P)H oxidase activity and reduction in angiotensin AT1-receptor expression, statins ameliorate angiotensin II-induced generation and release of reactive oxygen species ( ROS). Statin-mediated induction of HO-1 has the potential to exert anti-adhesive, anti-oxidant and anti-apoptotic effects. Inhibition of Rho-Rho-associated kinases (ROCK) by statins leading to activation of KLF2 and PPARα may induce eNOS, complement-inhibitory, anti-oxidant and anti-thrombotic genes. RhoA inhibition also enhances ecto-5′-nucleotidase (Ecto-5′-Nu, CD73) cell surface expression and activity, so increasing extracellular adenosine which modulates vascular tone, inhibits platelet activation and leukocyte adhesion.
References
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