Statins have been shown to possess multiple antiinflammatory actions that play an important role in mediating their vasculoprotective properties. Conditions associated with impairment of NO availability and increased oxidant stress, such as hypoxia and ischemia-reperfusion, induce an inflammatory endothelial phenotype characterized by enhanced expression of the surface adhesion molecules, P-selectin, ICAM-1, and VCAM-1. By enhancing eNOS function and reducing ROS, statins decrease expression of adhesion molecules and inhibit leukocyte-EC binding and transmigration in vitro at concentrations as low as 0.01 ||M. In animal models, statins decrease leukocyte adhesion within the microvasculature in response to thrombin, bacterial toxins, and low-dose LNMA. High-dose LNMA reverses these effects, and they are not observed in eNOS knockout mice. Statins may directly inhibit the transcription factors NF-kB and activator protein-1 (AP-1), and induce the nuclear receptors PPARa and g which regulate inflammatory responses in EC. Anti-inflammatory effects on leukocytes have also been demonstrated, consisting of decreased expression of integrins, which mediate binding to EC, and proinflammatory cytokines.
T-lymphocyte-mediated immune responses are primarily responsible for allograft rejection after organ transplantation. An increasingly important role for T cells is now being recognized in mediating the inflammatory phenotype of the microvasculature in response to injurious stimuli such as ischemia-reperfusion and hypercholesterolemia. High concentrations (1 to 10 ||M) of simvastatin completely block interferon-g induction of MHC class II antigen on microvascular ECs. A similar effect is noted in monocytes-macrophages, but not in highly specialized antigen-presenting dendritic cells and B-lymphocytes. This effect is mediated through transcriptional inhibition of promoter IV of the MHC II transactivator, CIITA, and is completely reversed by mevalonate or GGPP. The consequences repressing MHC II induction are an inhibition of T-lymphocyte proliferation and IL-2 release upon exposure to allogeneic EC or macrophages.
All the anti-inflammatory effects of statins just described are dependent on HMG CoA reductase inhibition, in that they can be blocked by mevalonate. A novel HMG CoA reductase-independent mechanism has been demonstrated consisting of allosteric inhibition of lymphocyte function antigen-1 (LFA-1) by binding to a novel L-(lovastatin) site within the molecule, locking it in an inactive state. As a result, LFA-1 mediated adhesion of leukocytes with the corresponding ligand on EC (ICAM-1) is inhibited, as is lymphocyte costimulation. Based on this discovery, researchers designed a novel lovastatin-based LFA-1 inhibitor that inhibits T-cell costimulation at concentrations of around 0.01 | M compared with 1 | M for the parent compound .
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