Statin Effects on Vascular Wall Cell Proliferation and Survival

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As a result of inhibition of GGPP synthesis, statins inhibit cell proliferation and induce apoptosis. Simvastatin and other lipophilic statins, at concentrations of 1 to 10 mM, suppress proliferation and migration of both systemic and pulmonary VSMC in the presence of serum or growth factors such as PDGF. A direct effect on the cytoskeleton or changes in gene expression could underlie the antiprolifera-tive effects of statins, such as an upregulation of the cyclin-dependent kinase inhibitor p27kip1. In serum-free conditions, statins induce apoptosis in a concentration

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Figure 2 Effect of simvastatin on endothelial cell (EC) cytoskeletal rearrangement. Relative to vehicle controls, ECs treated with simvastatin (5 ||M, 16 hours) demonstrate enhanced cortical actin (small arrows) and reduced central stress fibers. Additionally, upon thrombin stimulation (1U, 5 minutes) few paracellular gaps are observed in simvastatin-treated cells compared to vehicle controls (large arrows). Bar = 10 ||m. (see color insert)

Figure 2 Effect of simvastatin on endothelial cell (EC) cytoskeletal rearrangement. Relative to vehicle controls, ECs treated with simvastatin (5 ||M, 16 hours) demonstrate enhanced cortical actin (small arrows) and reduced central stress fibers. Additionally, upon thrombin stimulation (1U, 5 minutes) few paracellular gaps are observed in simvastatin-treated cells compared to vehicle controls (large arrows). Bar = 10 ||m. (see color insert)

dependent manner with as little as 0.5 |mM having an effect. Downregulation of Bcl-2 and consequent caspase activation may mediate apoptosis.

Moderate to high concentrations of statins (> 0.1 ||M atorvastatin) similarly inhibit EC proliferation and migration and induce apoptosis, thereby impairing angiogenesis. In contrast, low concentrations (0.01 to 0.05 ||M) enhance VEGF release, upregulate VEGF receptor 2, induce proliferation, inhibit hypoxia-induced apoptosis, and increase EC migration by up to 75 percent. These actions promote capillary tube formation in vitro, that is, angiogenesis, similar to VEGF stimulation. In mice, inflammation induced angiogenesis is enhanced by low dose (0.5mg/kg/day) atorvastatin, whereas high-dose therapy (2.5mg/kg/day) is inhibitory and also reduces tumor angiogenesis [6]. The high-dose antiangiogenic properties of statins are reversed by GGPP, indicating that inhibition of Rho prenylation is responsible. The mechanisms mediating EC survival in response to low concentrations of statins are not completely understood. They are reversed by mevalonate, but not by Rho-kinase inhibitors. The proangiogenic effects of statins are linked to phosphorylation and activation of Akt at serine 473 and subsequent eNOS Ser1177 phosphorylation and activation, which are observed at very low concentrations (0.0001 |M atorvastatin) and remain evident with higher concentrations. Phosphatidylinositol-3-kinase inhibition reverses low-dose statin effects on EC indicating activation of the PI3K/Akt pathway. Provision of mevalonate also blocks statin-inducted Akt activation. Whether GGPP also blocks low-dose statin effects on ECs is unknown. Activation of eNOS may be ultimately responsible since NOS inhibition by LNMA prevents the EC stimulating effects of statins in some studies. Importantly, Akt activation is not observed in VSMCs.

In addition to angiogenesis (sprouting of EC from preexisting capillaries), the mobilization and incorporation of bone-marrow derived endothelial progenitor cells (EPCs) is a mechanism of postnatal neovascularization. Statins, in a fashion similar to VEGF, increase circulating EPCs in animals and humans and activates EPCs (increased adhesion, proliferation, survival). These actions are also mediated by activation of the PI3K/Akt pathway, but are not reversed by LNMA, GGPP, or Rho-kinase inhibitors. Similar to the effects on mature ECs, however, mevalonate prevents EPC differentiation [7].

Investigators have recently begun to dissect the path-way(s) involved in statin-mediated activation of Akt/PKB in endothelial cells [8]. Within 10 minutes of application of simvastatin, membrane protrusions (lamellipodia and filopodia) and ruffles are formed and Akt is translocated from the nucleus and cytoplasm to these sites, accompanied by increased phosphorylation of Akt. Mevalonate or cholesterol repletion prevents these changes, as does PI3K inhibition. This is in contrast to VEGF-mediated Akt activation, which is not affected by cholesterol loading. Depletion of cholesterol from lipid rafts in the membrane may thus underlie statin-induced Akt activation. Alternatively, the membrane changes observed are reminiscent of Rac and Cdc42 activation. As mentioned previously, there is evidence to suggest that statins increase active GTP-bound Rac, while reducing membrane translocation. Moreover, Ras, which acts upstream of PI3K, has been found to be activated by statins, and statin-mediated Akt phosphorylation in EC is inhibited by overexpression of a dominant-negative

Ras mutant. The PI3K/Akt signaling pathway is highly complex, and the exact mechanism of activation by statins is not clear; however, inhibition of Rho prenylatin may not be primarily responsible.

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