Activation of sphingosine-1-phosphate signalling as a potential underlying mechanism of the pleiotropic effects of statin therapy

References

• Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–81
   PubMed Web of Science ®Google Scholar
• Sacks FM, Gibson CM, Rosner B, et al. The influence of pretreatment low density lipoprotein cholesterol concentrations on the effect of hypocholesterolemic therapy on coronary atherosclerosis in angiographic trials. Harvard Atherosclerosis Reversibility Project Research Group. Am J Cardiol 1995;76:78C–85C
   Google Scholar
• Thompson GR, Hollyer J, Waters DD. Percentage change rather than plasma level of LDL-cholesterol determines therapeutic response in coronary heart disease. Curr Opin Lipidol 1995;6:386–8
   PubMedGoogle Scholar
• Bhatnagar D, Soran H, Durrington PN. Hypercholesterolaemia and its management. BMJ 2008;337:a993 . doi: 10.1136/bmj.a993
   PubMed Web of Science ®Google Scholar
• The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Am J Cardiol 1993;72:1031–7
   Google Scholar
• Furberg CD, Byington RP, Crouse JR, Espeland MA. Pravastatin, lipids, and major coronary events. Am J Cardiol 1994;73:1133–4
   Google Scholar
• Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:III39–43
   PubMed Web of Science ®Google Scholar
• Ramasubbu K, Estep J, White DL, et al. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol 2008;51:415–26
   PubMed Web of Science ®Google Scholar
• Egom EE, Ke Y, Musa H, et al. FTY720 prevents ischemia/reperfusion injury-associated arrhythmias in an ex vivo rat heart model via activation of Pak1/Akt signaling. J Mol Cell Cardiol 2010;48:406–14
   PubMed Web of Science ®Google Scholar
• Egom EE, Ke Y, Solaro RJ, Lei M. Cardioprotection in ischemia/reperfusion injury: spotlight on sphingosine-1-phosphate and bradykinin signalling. Prog Biophys Mol Biol 2010;103:142–7
   Google Scholar
• Egom EE, Mamas MA, Clark AL. The potential role of sphingolipid-mediated cell signaling in the interaction between hyperglycemia, acute myocardial infarction and heart failure. Expert Opin Ther Targets 2012;16:791–800
   PubMed Web of Science ®Google Scholar
• Egom EE, Mohamed TM, Mamas MA, et al. Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury. Am J Physiol Heart Circ Physiol 2011;301:H1487–95
   Google Scholar
• Kontush A, Therond P, Zerrad A, et al. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities. Arterioscler Thromb Vasc Biol 2007;27:1843–9
   PubMed Web of Science ®Google Scholar
• Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res 2006;98:1352–64
   PubMed Web of Science ®Google Scholar
• Barter PJ, Puranik R, Rye KA. New insights into the role of HDL as an anti-inflammatory agent in the prevention of cardiovascular disease. Curr Cardiol Rep 2007;9:493–8
   PubMedGoogle Scholar
• Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 2003;4:397–407
   PubMed Web of Science ®Google Scholar
• Walter DH, Rochwalsky U, Reinhold J, et al. Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler Thromb Vasc Biol 2007;27:275–82
   PubMed Web of Science ®Google Scholar
• Nofer JR, Bot M, Brodde M, et al. FTY720, a synthetic sphingosine 1 phosphate analogue, inhibits development of atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2007;115:501–8
   PubMed Web of Science ®Google Scholar
• Igarashi J, Miyoshi M, Hashimoto T, et al. Statins induce S1P1 receptors and enhance endothelial nitric oxide production in response to high-density lipoproteins. Br J Pharmacol 2007;150:470–9
   PubMed Web of Science ®Google Scholar
• Sugiura T, Dohi Y, Yamashita S, et al. Analytical evaluation of plasma serotonin and sphingosine 1-phosphate and their clinical assessment in early atherosclerosis. Coron Artery Dis 2012;23:234–8
   Google Scholar
• West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440–5
   Google Scholar
• P D. Hyperlipidaemia diagnosis and management. 3rd ed. London: Hodder Arnold; 2007
   Google Scholar
• Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001;103:926–33
   PubMed Web of Science ®Google Scholar
• Schartl M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation 2001;104:387–92
   PubMed Web of Science ®Google Scholar
• Williams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 1998;31:684–91
   PubMed Web of Science ®Google Scholar
• Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001;104:249–52
   PubMed Web of Science ®Google Scholar
• Corti R, Fuster V, Fayad ZA, et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 2002;106:2884–7
   PubMed Web of Science ®Google Scholar
• McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 2004;363:2015–21
   PubMed Web of Science ®Google Scholar
• Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64–70
   PubMed Web of Science ®Google Scholar
• Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction. Circulation 2002;106:1447–52
   PubMed Web of Science ®Google Scholar
• Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230–5
   PubMed Web of Science ®Google Scholar
• Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488–93
   PubMed Web of Science ®Google Scholar
• Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994;89:2519–24
   PubMed Web of Science ®Google Scholar
• Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481–7
   PubMed Web of Science ®Google Scholar
• Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation 1999;99:3227–33
   PubMed Web of Science ®Google Scholar
• Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005;111:2356–63
   PubMed Web of Science ®Google Scholar
• Liu PY, Liu YW, Lin LJ, et al. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation 2009;119:131–8
   PubMed Web of Science ®Google Scholar
• Tsunekawa T, Hayashi T, Kano H, et al. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 2001;104:376–9
   PubMed Web of Science ®Google Scholar
• Vita JA, Yeung AC, Winniford M, et al. Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease. Circulation 2000;102:846–51
   PubMedGoogle Scholar
• Yokoyama I, Momomura S, Ohtake T, et al. Improvement of impaired myocardial vasodilatation due to diffuse coronary atherosclerosis in hypercholesterolemics after lipid-lowering therapy. Circulation 1999;100:117–22
   Google Scholar
• John S, Schlaich M, Langenfeld M, et al. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: a randomized, placebo-controlled, double-blind study. Circulation 1998;98:211–6
   PubMed Web of Science ®Google Scholar
• Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW. Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. J Am Coll Cardiol 1999;33:234–41
   PubMed Web of Science ®Google Scholar
• Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation 2002;105:933–8
   PubMed Web of Science ®Google Scholar
• van Nieuw Amerongen GP, Vermeer MA, Negre-Aminou P, et al. Simvastatin improves disturbed endothelial barrier function. Circulation 2000;102:2803–9
   Google Scholar
• Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001;103:276–83
   PubMed Web of Science ®Google Scholar
• Dangas G, Badimon JJ, Smith DA, et al. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 1999;33:1294–304
   PubMed Web of Science ®Google Scholar
• Eto M, Kozai T, Cosentino F, et al. Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation 2002;105:1756–9
   PubMed Web of Science ®Google Scholar
• Szczeklik A, Musial J, Undas A, et al. Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 1999;33:1286–93
   PubMed Web of Science ®Google Scholar
• Undas A, Brummel KE, Musial J, et al. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001;103:2248–53
   PubMed Web of Science ®Google Scholar
• Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med 2008;14:37–44
   PubMed Web of Science ®Google Scholar
• Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circulation J 2010;74:818–26
   PubMed Web of Science ®Google Scholar
• Rashid M, Tawara S, Fukumoto Y, et al. Importance of Rac1 signaling pathway inhibition in the pleiotropic effects of HMG-CoA reductase inhibitors. Circulation J 2009;73:361–70
   PubMed Web of Science ®Google Scholar
• Tanaka S, Fukumoto Y, Nochioka K, et al. Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol 2013;33:1591--600
   PubMed Web of Science ®Google Scholar
• Javelaud D, Mauviel A. Mammalian transforming growth factor-betas: smad signaling and physio-pathological roles. Int J Biochem Cell Biol 2004;36:1161–5
   PubMed Web of Science ®Google Scholar
• Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783–810
   PubMed Web of Science ®Google Scholar
• Porreca E, Di Febbo C, Baccante G, et al. Increased transforming growth factor-beta(1) circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin. J Am Coll Cardiol 2002;39:1752–7
   PubMed Web of Science ®Google Scholar
• Rodriguez-Vita J, Sánchez-Galán E, Santamaría B, et al. Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation. PLoS One 2008;3:e3959 . doi:10.1371/journal.pone.0003959
   Google Scholar
• Rodrigues Diez R, Rodrigues-Díez R, Lavoz C, et al. Statins inhibit angiotensin II/Smad pathway and related vascular fibrosis, by a TGF-beta-independent process. PLoS One 2010;5:e14145 . doi:10.1371/journal.pone.0014145
   Google Scholar
• Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001;108:391–7
   PubMed Web of Science ®Google Scholar
• Hussein O, Schlezinger S, Rosenblat M, et al. Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL. Atherosclerosis 1997;128:11–8
   PubMed Web of Science ®Google Scholar
• Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001;108:399–405
   PubMed Web of Science ®Google Scholar
• Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 1997;30:1212–7
   PubMed Web of Science ®Google Scholar
• Okajima F. Plasma lipoproteins behave as carriers of extracellular sphingosine 1-phosphate: is this an atherogenic mediator or an anti-atherogenic mediator? Biochim Biophys Acta 2002;1582:132–7
   PubMed Web of Science ®Google Scholar
• Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 2005;118:4605–12
   PubMed Web of Science ®Google Scholar
• Egom EE, Mamas MA, Chacko S, et al. Serum sphingolipids level as a novel potential marker for early detection of human myocardial ischaemic injury. Front Physiol 2013;4:130 . doi: 10.3389/fphys.2013.00130
   Google Scholar
• Deutschman DH, Carstens JS, Klepper RL, et al. Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate. Am Heart J 2003;146:62–8
   PubMed Web of Science ®Google Scholar
• Sattler KJ, Elbasan S, Keul P, et al. Sphingosine 1-phosphate levels in plasma and HDL are altered in coronary artery disease. Basic Res Cardiol 2010;105:821–32
   PubMed Web of Science ®Google Scholar
• Yatomi Y, Ruan F, Hakomori S, Igarashi Y. Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood 1995;86:193–202
   PubMed Web of Science ®Google Scholar
• Tani M, Sano T, Ito M, Igarashi Y. Mechanisms of sphingosine and sphingosine 1-phosphate generation in human platelets. J Lipid Res 2005;46:2458–67
   PubMed Web of Science ®Google Scholar
• Pappu R, Schwab SR, Cornelissen I, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007;316:295–8
   PubMed Web of Science ®Google Scholar
• Ito K, Anada Y, Tani M, et al. Lack of sphingosine 1-phosphate-degrading enzymes in erythrocytes. Biochem Biophys Res Commun 2007;357:212–7
   PubMed Web of Science ®Google Scholar
• Hanel P, Andreani P, Graler MH. Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB J 2007;21:1202–9
   PubMed Web of Science ®Google Scholar
• Ancellin N, Colmont C, Su J, et al. Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation. J Biol Chem 2002;277:6667–75
   PubMed Web of Science ®Google Scholar
• Murata N, Sato K, Kon J, et al. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem J 2000;352:809–15
   PubMed Web of Science ®Google Scholar
• Nofer JR, van der Giet M, Tolle M, et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 2004;113:569–81
   PubMed Web of Science ®Google Scholar
• Theilmeier G, Schmidt C, Herrmann J, et al. High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation 2006;114:1403–9
   PubMed Web of Science ®Google Scholar
• Assmann G, Nofer JR. Atheroprotective effects of high-density lipoproteins. Annu Rev Med 2003;54:321–41
   PubMed Web of Science ®Google Scholar
• Egom EE, Mamas MA, Soran H. HDL quality or cholesterol cargo: what really matters – spotlight on sphingosine-1-phosphate-rich HDL. Curr Opin Lipidol 2013. doi: 10.1097/MOL.0b013e328361f822
   Google Scholar
• Vessey DA, Li L, Honbo N, Karliner JS. Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning. Am J Physiol Heart Circ Physiol 2009;297:H1429–35
   Google Scholar
• Karliner JS. Sphingosine kinase and sphingosine 1-phosphate in cardioprotection. J Cardiovasc Pharmacol 2009;53:189–97
   PubMed Web of Science ®Google Scholar
• Ontaneda D, Cohen JA. Potential mechanisms of efficacy and adverse effects in the use of fingolimod (FTY720). Expert review of clinical pharmacology 2011;4:567–70
   PubMedGoogle Scholar
• Mullershausen F, Zecri F, Cetin C, et al. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol 2009;5:428–34
   PubMed Web of Science ®Google Scholar
• Hofmann U, Hu K, Walter F, et al. Pharmacological pre- and post-conditioning with the sphingosine-1-phosphate receptor modulator FTY720 after myocardial ischaemia-reperfusion. Br J Pharmacol 2010;160:1243–51
   Google Scholar
• Keul P, Tolle M, Lucke S, et al. The sphingosine-1-phosphate analogue FTY720 reduces atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2007;27:607–13
   PubMed Web of Science ®Google Scholar
• Okajima F, Sato K, Kimura T. Anti-atherogenic actions of high-density lipoprotein through sphingosine 1-phosphate receptors and scavenger receptor class B type I. Endocr J 2009;56:317–34
   Google Scholar
• Watterson KR, Ratz PH, Spiegel S. The role of sphingosine-1-phosphate in smooth muscle contraction. Cell Signal 2005;17:289–98
   PubMed Web of Science ®Google Scholar
• Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 2007;115:84–105
   PubMed Web of Science ®Google Scholar
• Han Y, Ciuffreda KJ, Selenow A, Ali SR. Dynamic interactions of eye and head movements when reading with single-vision and progressive lenses in a simulated computer-based environment. Invest Ophthalmol Vis Sci 2003;44:1534–45
   PubMed Web of Science ®Google Scholar
• Takuwa Y, Okamoto H, Takuwa N, et al. Subtype-specific, differential activities of the EDG family receptors for sphingosine-1-phosphate, a novel lysophospholipid mediator. Mol Cell Endocrinol 2001;177:3–11
   Google Scholar
• Fukushima N, Ishii I, Contos JJ, et al. Lysophospholipid receptors. Annu Rev Pharmacol Toxicol 2001;41:507–34
   PubMed Web of Science ®Google Scholar
• Choi JW, Lee CW, Chun J. Biological roles of lysophospholipid receptors revealed by genetic null mice: an update. Biochim Biophys Acta 2008;1781:531–9
   Google Scholar
• Liu Y, Wada R, Yamashita T, et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 2000;106:951–61
   PubMed Web of Science ®Google Scholar
• Strub GM, Maceyka M, Hait NC, et al. Extracellular and intracellular actions of sphingosine-1-phosphate. Adv Exp Med Biol 2010;688:141–55
   PubMed Web of Science ®Google Scholar
• MacLennan AJ, Benner SJ, Andringa A, et al. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function. Hear Res 2006;220:38–48
   Google Scholar
• Skoura A, Sanchez T, Claffey K, et al. Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. J Clin Invest 2007;117:2506–16
   PubMed Web of Science ®Google Scholar
• Ishii I, Fukushima N, Ye X, Chun J. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem 2004;73:321–54
   PubMed Web of Science ®Google Scholar
• Alewijnse AE, Peters SL, Michel MC. Cardiovascular effects of sphingosine-1-phosphate and other sphingomyelin metabolites. Br J Pharmacol 2004;143:666–84
   PubMed Web of Science ®Google Scholar
• Czyborra C, Bischoff A, Michel MC. Indomethacin differentiates the renal effects of sphingosine-1-phosphate and sphingosylphosphorylcholine. Naunyn Schmiedebergs Arch Pharmacol 2006;373:37–44
   Google Scholar
• Hemmings DG. Signal transduction underlying the vascular effects of sphingosine 1-phosphate and sphingosylphosphorylcholine. Naunyn Schmiedebergs Arch Pharmacol 2006;373:18–29
   PubMed Web of Science ®Google Scholar
• Van Brocklyn JR, Lee MJ, Menzeleev R, et al. Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. J Cell Biol 1998;142:229–40
   PubMed Web of Science ®Google Scholar
• Rosenfeldt HM, Hobson JP, Maceyka M, et al. EDG-1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration. FASEB J 2001;15:2649–59
   PubMed Web of Science ®Google Scholar
• Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000;6:1004–10
   PubMed Web of Science ®Google Scholar
• Lefer AM, Campbell B, Shin YK, et al. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 1999;100:178–84
   PubMed Web of Science ®Google Scholar
• Pruefer D, Scalia R, Lefer AM. Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler Thromb Vasc Biol 1999;19:2894–900
   PubMed Web of Science ®Google Scholar
• Qian H, Neplioueva V, Shetty GA, et al. Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits. Circulation 1999;99:2979–82
   PubMed Web of Science ®Google Scholar
• Simon DI, Stamler JS, Jaraki O, et al. Antiplatelet properties of protein S-nitrosothiols derived from nitric oxide and endothelium-derived relaxing factor. Arterioscler Thromb 1993;13:791–9
   PubMedGoogle Scholar
• Greenwood J, Mason JC. Statins and the vascular endothelial inflammatory response. Trends Immunol 2007;28:88–98
   PubMed Web of Science ®Google Scholar
• Ii M, Losordo DW. Statins and the endothelium. Vascul Pharmacol 2007;46:1–9
   PubMed Web of Science ®Google Scholar
• Brenner B, Koppenhoefer U, Weinstock C, et al. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J Biol Chem 1997;272:22173–81
   PubMed Web of Science ®Google Scholar
• Xin C, Ren S, Eberhardt W, et al. The immunomodulator FTY720 and its phosphorylated derivative activate the Smad signalling cascade and upregulate connective tissue growth factor and collagen type IV expression in renal mesangial cells. Br J Pharmacol 2006;147:164–74
   PubMed Web of Science ®Google Scholar
• Takuwa N, Ohkura S, Takashima S, et al. S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. Cardiovasc Res 2010;85:484–93
   PubMed Web of Science ®Google Scholar
• Ikeda H, Watanabe N, Ishii I, et al. Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. J Lipid Res 2009;50:556–64
   PubMed Web of Science ®Google Scholar
• Shea BS, Brooks SF, Fontaine BA, et al. Prolonged exposure to sphingosine 1-phosphate receptor-1 agonists exacerbates vascular leak, fibrosis, and mortality after lung injury. Am J Respir Cell Mol Biol 2010;43:662–73
   PubMed Web of Science ®Google Scholar
• Keller CD, Rivera Gil P, Tolle M, et al. Immunomodulator FTY720 induces myofibroblast differentiation via the lysophospholipid receptor S1P3 and Smad3 signaling. Am J Pathol 2007;170:281–92
   PubMedGoogle Scholar
• Davaille J, Li L, Mallat A, Lotersztajn S. Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts. J Biol Chem 2002;277:37323–30
   PubMed Web of Science ®Google Scholar
• Sato M, Markiewicz M, Yamanaka M, et al. Modulation of transforming growth factor-beta (TGF-beta) signaling by endogenous sphingolipid mediators. J Biol Chem 2003;278:9276–82
   Google Scholar
• Kimura T, Mogi C, Tomura H, et al. Induction of scavenger receptor class B type I is critical for simvastatin enhancement of high-density lipoprotein-induced anti-inflammatory actions in endothelial cells. J Immunol 2008;181:7332–40
   Google Scholar
• Rodriguez C, Gonzalez-Diez M, Badimon L, Martinez-Gonzalez J. Sphingosine-1-phosphate: a bioactive lipid that confers high-density lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin. Thromb Haemost 2009;101:665–73
   Google Scholar
• Kimura T, Sato K, Tomura H, Okajima F. Cross-talk between exogenous statins and endogenous high-density lipoprotein in anti-inflammatory and anti-atherogenic actions. Endocr Metab Immune Disord Drug Targets 2010;10:8–15
   Google Scholar
• Liao JK. Isoprenoids as mediators of the biological effects of statins. J Clin Invest 2002;110:285–8
   PubMed Web of Science ®Google Scholar
• Graaf MR, Richel DJ, van Noorden CJ, Guchelaar HJ. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer treatment reviews 2004;30:609–41
   PubMed Web of Science ®Google Scholar
• Hooff GP, Wood WG, Muller WE, Eckert GP. Isoprenoids, small GTPases and Alzheimer’s disease. Biochim Biophys Acta 2010;1801:896–905
   PubMed Web of Science ®Google Scholar
• Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 2007;40:575–84
   PubMed Web of Science ®Google Scholar
• Dantas AP, Igarashi J, Michel T. Sphingosine 1-phosphate and control of vascular tone. Am J Physiol Heart Circ Physiol 2003;284:H2045–52
   PubMed Web of Science ®Google Scholar
• Hla T. Signaling and biological actions of sphingosine 1-phosphate. Pharmacol Res 2003;47:401–7
   PubMed Web of Science ®Google Scholar
• Kimura T, Sato K, Kuwabara A, et al. Sphingosine 1-phosphate may be a major component of plasma lipoproteins responsible for the cytoprotective actions in human umbilical vein endothelial cells. J Biol Chem 2001;276:31780–5
   PubMed Web of Science ®Google Scholar
• Kwon YG, Min JK, Kim KM, et al. Sphingosine 1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. J Biol Chem 2001;276:10627–33
   PubMed Web of Science ®Google Scholar
• Rikitake Y, Hirata K, Kawashima S, et al. Involvement of endothelial nitric oxide in sphingosine-1-phosphate-induced angiogenesis. Arterioscler Thromb Vasc Biol 2002;22:108–14
   PubMed Web of Science ®Google Scholar
• Lee MJ, Thangada S, Claffey KP, et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 1999;99:301–12
   PubMed Web of Science ®Google Scholar
• Inoki I, Takuwa N, Sugimoto N, et al. Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor. Biochem Biophys Res Commun 2006;346:293–300
   Web of Science ®Google Scholar