HMG-CoA Reductase Inhibitors Suppress Intracellular Calcium Mobilization and Membrane Current Induced by Lysophosphatidylcholine in Endothelial Cells

Abstract

Background — Lysophosphatidylcholine (LPC) is known to increase intracellular Ca 2+ concentration ([Ca 2+ ] i ) in endothelial cells. This study was conducted to investigate the effects of HMG-CoA reductase inhibitors (statins) on the increase in [Ca 2+ ] i and membrane current induced by LPC. Methods and Results — [Ca 2+ ] i was determined in cultured human aortic endothelial cells by fura-2 assay, and membrane current was measured by whole-cell patch clamp. The [Ca 2+ ] i increase induced by LPC was abolished by inhibitors of phospholipase C (PLC). Statins markedly decreased the [Ca 2+ ] i increase caused by LPC. This suppressive effect was quickly reversed by geranylgeranylpyrophosphate (GGPP) and was mimicked by inhibitors of Rho and Rho kinase. LPC induced the translocation of the GTP-bound active form of RhoA into membranes within 1 minute as determined by a pull-down assay and reduced the levels of RhoA in the cytoplasm, indicating that LPC quickly increases the GTP/GDP ratio of RhoA and induces membrane translocation. Statins prevented the GTP/GDP exchange of RhoA and its membrane translocation from the cytoplasm caused by LPC, and these effects of statins were reversed by GGPP. The responses of RhoA activation to statins and GGPP concurred with their effects on Ca 2+ mobilization. LPC also induced a nonselective cation current after a lag. Statins prolonged the lag and decreased the current amplitude, and GGPP abolished the inhibitory effect on the current. Conclusions — LPC induced Ca 2+ mobilization and membrane current via a Rho activation–dependent PLC pathway in endothelial cells, and statins blocked these effects by preventing the GGPP-dependent lipid modification of Rho. The present study implicates Rho in LPC stimulation of Ca 2+ movement.