Lysophosphatidic acid pretreatment prevents micromolar atorvastatin-induced endothelial cell death and ensures the beneficial effects of high-concentration statin therapy on endothelial gene expression

Abstract

Because of the pleiotropic effects of statins, it may potentially be used as a locoregional adjuvant in vascular revascularization, tissue engineering, and regenerative procedures. Electron probe X-ray microanalyses and oligonucleotide microarrays were used to identify the global effects of micromolar concentrations of atorvastatin on the gene expression and cell viability of endothelial cells in different states of lysophosphatidic acid (LPA)-induced activation. Treatment with 1-μM atorvastatin for 24 hours significantly reduced the viability of human vascular endothelial cells (HUVECs). However, the same treatment of LPA-preactivated HUVECs produced elevated cell viability levels and an optimal vascular gene expression profile, including endothelial nitric oxide synthase overexpression, endothelin-1 repression, an anti-inflammatory genetic pattern, and upregulation of molecules involved in maintaining the endothelial barrier (vascular endothelial cadherin, claudin 5, tight junction protein 1, integrin β4). The atorvastatin treatment also produced a repression of microRNA 21 and genes involved in cell proliferation and neointimal formation (vascular endothelial growth factor [VEGF] A, VEGF receptor 1, VEGFC). Results obtained suggest that micromolar atorvastatin therapy can enhance global endothelial function, but its effects on cell viability vary according to the baseline state of cell activation (preactivated, postactivated, or not activated). Preactivation with LPA protects HUVECs against atorvastatin-induced apoptosis and delivers optimal levels of cell viability and functionality.