The statins, a class of HMG CoA-reductase inhibitors, are used clinically for their ability to lower serum cholesterol levels and reduce the morbidity and mortality associated with coronary artery disease. However, not all of their clinical benefits can be attributed to their lipid-lowering properties. We have previously reported the direct effects of simvastatin on endothelial cells (ECs), including the up-regulation of integrin β4 gene and protein expression. Whereas the role of integrins has been described with respect to a variety of pathways, including both Rho GTPase and MAP kinase signaling, the role of integrin β4 in EC signaling is poorly characterized. In this study, human pulmonary artery ECs treated with simvastatin (5 μM, 16 hours) demonstrated a significant increase in both cytosolic Rac activation (Rac-GTP) and integrin β4 protein expression (95% and 50%, respectively). Compared with controls, simvastatin-induced (5 μM, 16 hours) Rac activation was markedly attenuated in ECs transfected with siRNA specific for integrin β4 (38% decrease), with no change in total Rac noted. Additionally, LPS-induced (5 μg/mL, 10 minutes) Erk phosphorylation was inhibited in ECs treated with simvastatin (5 μM, 16 hours), an effect that may contribute to the antiangiogenic properties of statins, whereas Erk phosphorylation was significantly enhanced in ECs transfected with integrin β4 siRNA (100% increase). Finally, RT-PCR confirmed that IL-8 RNA was markedly increased in integrin β4-silenced ECs compared with control cells (≈threefold increase), whereas LPS-induced (5 μg/mL, 10 minutes) IL-8 expression was significantly attenuated in simvastatin-treated (5 μM, 16 hours) ECs compared with LPS alone (30% decrease), findings that may account for the anti-inflammatory properties of statins. Our results indicate a novel regulatory mechanism of Rac and Erk activities and the expression of IL-8 in ECs that is mediated by integrin β4. These data advance our understanding of the complex effects of statins on EC signaling and may ultimately lead to the identification of novel clinical targets.
Funding: HL077134-01, Parker B. Francis Fellowship.
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