Simvastatin enhances endothelial differentiation of peripheral blood mononuclear cells in hypercholesterolemic patients and induces pro-angiogenic cytokine IL-8 secretion from monocytes

Abstract

BACKGROUND: Statins are known to have pleiotropic effects. We examined the effect and mechanism of simvastatin therapy on EPC differentiation and pro-angiogenic cytokines in patients with hypercholesterolemia. METHODS: Twenty-two hypercholesterolemia patients without any other modifiable cardiovascular risk factors or history of previous lipid-lowering therapy were given simvastatin 20 mg/day for 4 weeks. Blood were drawn pre- and post-therapy. The in vitro effects of simvastatin were studied in a separate set of experiments. RESULTS: Simvastatin treatment significantly increased the number of DiI-acLDL, UEA-1 lectin double-positive EPCs and facilitated its appearance. By FACS analysis of freshly isolated PBMNCs, KDR (+) cells increased after simvastatin treatment while there were no differences in CD34, AC133, and VE-cadherin. Also, serum concentration of IL-8 was markedly increased, while VEGF was only slightly increased. In vitro, PBMNCs co-cultured with simvastatin showed increased cluster formation at day 7, and simvastatin facilitated the appearance and networking of EPCs compared with vehicle. Simvastatin-co-cultured PBMNCs showed significantly increased KDR (+) cells, in contrast to CD34, CD31, and VE-Cadherin (+) cells. In response to simvastatin, IL-8 was mainly increased in monocyte culture supernatants while VEGF increased in smooth muscle cell culture supernatants. These cytokines were associated with increased EPC migratory function. The increase in IL-8 secretion from monocytes by statin treatment was associated with phosphorylation and inactivation of GSK3beta, which was reversed by constitutive activation of GSK-3beta. CONCLUSION: Simvastatin enhances endothelial differentiation of peripheral blood mononuclear cells in patients with hypercholesterolemia and increases pro-angiogenic cytokine IL-8 secretion from monocytes. Our results may explain the pro-angiogenic effects associated with statin therapy and offer further evidence of statin pleiotropism.