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Atorvastatin prevents hypoxia-induced inhibition of endothelial nitric oxide synthase expression but does not affect heme oxygenase-1 in human microvascular endothelial cells

      Abstract

      Beneficial cardiovascular effects of statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are particularly assigned to the modulation of inflammation. Endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) are listed among the crucial protective, anti-inflammatory genes in the vasculature. Here we show that atorvastatin at pharmacologically relevant concentration (0.1 μM) enhanced the expression of eNOS in human microvascular endothelial cells (HMEC-1). Moreover, atorvastatin prevented hypoxia-induced decrease in eNOS expression. However, in the same cells atorvastatin was ineffective in modulation of HO-1 protein level. Therefore, we suggest that the protective effect of statins at their pharmacological concentrations is not mediated by enhancement of HO-1 activity, but may involve eNOS.

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      References

        • Liao J.K.
        • Laufs U.
        Pleiotropic effects of statins.
        Annu Rev Pharmacol Toxicol. 2005; 45: 89-118
        • Dulak J.
        • Jozkowicz A.
        Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy.
        Curr Cancer Drug Targets. 2005; 5: 579-594
        • Morita T.
        Heme oxygenase and atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1786-1795
        • Grosser N.
        • Abate A.
        • Oberle S.
        • et al.
        Heme oxygenase-1 induction may explain the antioxidant profile of aspirin.
        Biochem Biophys Res Commun. 2003; 308: 956-960
        • Visner G.A.
        • Lu F.
        • Zhou H.
        • Liu J.
        • Kazemfar K.
        • Agarwal A.
        Rapamycin induces heme oxygenase-1 in human pulmonary vascular cells: implications in the antiproliferative response to rapamycin.
        Circulation. 2003; 107: 911-916
        • Deng Y.M.
        • Wu B.J.
        • Witting P.K.
        • Stocker R.
        Probucol protects against smooth muscle cell proliferation by upregulating heme oxygenase-1.
        Circulation. 2004; 110: 1855-1860
        • Frick M.
        • Dulak J.
        • Cisowski J.
        • et al.
        Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells.
        Atherosclerosis. 2003; 170: 229-236
        • Dulak J.
        • Jozkowicz A.
        • Foresti R.
        • et al.
        Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells.
        Antioxid Redox Signal. 2002; 4: 229-240
        • Jeney V.
        • Balla J.
        • Yachie A.
        • et al.
        Pro-oxidant and cytotoxic effects of circulating heme.
        Blood. 2002; 100: 879-887
        • Laufs U.
        • Fata V.L.
        • Liao J.K.
        Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase.
        J Biol Chem. 1997; 272: 31725-31729
        • Laufs U.
        • La Fata V.
        • Plutzky J.
        • Liao J.K.
        Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors.
        Circulation. 1998; 97: 1129-1135
        • Grosser N.
        • Hemmerle A.
        • Berndt G.
        • et al.
        The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells.
        Free Radic Biol Med. 2004; 37: 2064-2071
        • Lee T.S.
        • Chang C.C.
        • Zhu Y.
        • Shyy J.Y.
        Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection.
        Circulation. 2004; 110: 1296-1302
        • Uchiyama T.
        • Atsuta H.
        • Utsugi T.
        • et al.
        Simvastatin induces heat shock factor 1 in vascular endothelial cells.
        Atherosclerosis. 2005; ([Epub ahead of print])
        • Grosser N.
        • Erdmann K.
        • Hemmerle A.
        • et al.
        Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1.
        Biochem Biophys Res Commun. 2004; 325: 871-876
        • Brown J.
        • Reading S.J.
        • Jones S.
        • et al.
        Critical evaluation of ECV304 as a human endothelial cell model defined by genetic analysis and functional responses: a comparison with the human bladder cancer derived epithelial cell line T24/83.
        Lab Invest. 2000; 80: 37-45
        • Thibault A.
        • Samid D.
        • Tompkins A.C.
        • et al.
        Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer.
        Clin Cancer Res. 1996; 2: 483-491
        • Cilla Jr., D.D.
        • Whitfield L.R.
        • Gibson D.M.
        • Sedman A.J.
        • Posvar E.L.
        Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects.
        Clin Pharmacol Ther. 1996; 60: 687-695
        • Kaneta S.
        • Satoh K.
        • Kano S.
        • Kanda M.
        • Ichihara K.
        All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells.
        Atherosclerosis. 2003; 170: 237-243
        • Muck A.O.
        • Seeger H.
        • Wallwiener D.
        Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.
        Z Kardiol. 2004; 93: 398-402
        • Urbich C.
        • Dernbach E.
        • Zeiher A.M.
        • Dimmeler S.
        Double-edged role of statins in angiogenesis signaling.
        Circ Res. 2002; 90: 737-744
        • Weis M.
        • Heeschen C.
        • Glassford A.J.
        • Cooke J.P.
        Statins have biphasic effects on angiogenesis.
        Circulation. 2002; 105: 739-745
        • Dichtl W.
        • Dulak J.
        • Frick M.
        • et al.
        HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells.
        Arterioscler Thromb Vasc Biol. 2003; 23: 58-63
        • Pradet-Balade B.
        • Boulme F.
        • Beug H.
        • Mullner E.W.
        • Garcia-Sanz J.A.
        Translation control: bridging the gap between genomics and proteomics?.
        Trends Biochem Sci. 2001; 26: 225-229
        • Nakayama M.
        • Takahashi K.
        • Kitamuro T.
        • et al.
        Repression of heme oxygenase-1 by hypoxia in vascular endothelial cells.
        Biochem Biophys Res Commun. 2000; 271: 665-671
        • Jazwa A.
        • Loboda A.
        • Golda S.
        • et al.
        Effect of heme and heme oxygenase-1 on VEGF synthesis and angiogenic potency of human keratinocytes.
        Free Radic Biol Med. 2006; 40: 1250-1263
        • Foresti R.
        • Motterlini R.
        The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis.
        Free Radic Res. 1999; 31: 459-475
        • Siow R.C.
        • Sato H.
        • Mann G.E.
        Heme oxygenase–carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide?.
        Cardiovasc Res. 1999; 41: 385-394