The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. (original) (raw)

• Goldstein, J.L. & Brown, M.S. Regulation of the mevalonate pathway. Nature 343, 425– 430 (1990).
  Article CAS Google Scholar
• ScandinavianSimvastatinSurvivalStudyGroup. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).
• Levine, G.N., Keaney Jr., J.F. & Vita, J.A. Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms. N. Engl. J. Med. 332, 512–521 ( 1995).
  Article CAS Google Scholar
• Sacks, F.M. et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335, 1001–1009 (1996).
  Article CAS Google Scholar
• WestofScotlandCoronaryPreventionStudyGroup. Influence of pravastatin and plasma lipids of clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 97 , 1440–1445 (1998).
• Endres, M. et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 95, 8880–8885 (1998).
  Article CAS Google Scholar
• Lefer, A.M. et al. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 100, 178–184 (1999).
  Article CAS Google Scholar
• Pruefer, D., Scalia, R. & Lefer, A.M. Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler. Thromb. Vasc. Biol. 19, 2894– 2900 (1999).
  Article CAS Google Scholar
• Osborne, J.A., Siegman, M.J., Sedar, A.W., Mooers, S.U. & Lefer, A.M. Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits. Am. J. Physiol. 256(3 Pt 1), C591– C597 (1989).
  Article CAS Google Scholar
• Lefer, A.M. & Lefer, D.J. The role of nitric oxide and cell adhesion molecules on the microcirculation in ischaemia-reperfusion. Cardiovasc. Res. 32, 743–751 (1996).
  Article CAS Google Scholar
• Dupuis, J., Tardif, J.-C., Cernacek, P. & Théroux, 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 99, 3227–3233 (1999).
  Article CAS Google Scholar
• Baller, D. et al. Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis. Circulation 99, 2871–2875 (1999).
  Article CAS Google Scholar
• Datta, S.R., Brunet, A. & Greenberg, M.E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).
  Article CAS Google Scholar
• Gerber, H.-P. et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway: Requirement for Flk-1/KDR activation. J. Biol. Chem. 273, 30336–30343 (1998).
  Article CAS Google Scholar
• Fujio, Y. & Walsh, K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner . J. Biol. Chem. 274, 16349– 16354 (1999).
  Article CAS Google Scholar
• Kim, I. et al. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Circ. Res. 86, 24–29 ( 2000).
  Article CAS Google Scholar
• Kontos, C.D. et al. Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt . Mol. Cell. Biol. 18, 4131– 4140 (1998).
  Article CAS Google Scholar
• Papapetropoulos, A. et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/Survivin pathway. J. Biol. Chem. 275, 9102–9105 (2000).
  Article CAS Google Scholar
• Carmeliet, P. et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147–157 ( 1999).
  Article CAS Google Scholar
• Fujio, Y., Nguyen, T., Wencker, D., Kitsis, R.N. & Walsh, K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 101, 660–667 (2000).
  Article CAS Google Scholar
• Fulton, D. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597 –601 (1999).
  Article CAS Google Scholar
• Dimmeler, S. et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399, 601–605 (1999).
  Article CAS Google Scholar
• Luo, Z. et al. Acute modulation of endothelial Akt/PKB activity alters NO-dependent vasomotor activity in vivo. J. Clin. Invest., In press. (2000).
• Morales-Ruiz, M. et al. Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. Circ. Res. 86, 892– 896 (2000).
  Article CAS Google Scholar
• Benjamin, L.E., Golijanin, D., Itin, A., Pode, D. & Keshet, E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Invest. 103, 159–165 (1999).
  Article CAS Google Scholar
• Alon, T. et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity . Nature. Med. 1, 1024– 1028 (1995).
  Article CAS Google Scholar
• Ziche, M. et al. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis . J. Clin. Invest. 99, 2625– 2634 (1997).
  Article CAS Google Scholar
• Murohara, T. et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J. Clin. Invest. 101, 2567 –2578 (1998).
  Article CAS Google Scholar
• Pu, L.Q. et al. Angiogenic growth factor and revascularization of the ischemic limb: evaluation in a rabbit model. J. Surg. Res. 54 , 575–583 (1993).
  Article CAS Google Scholar
• Simon, D.I. et al. Antiplatelet properties of protein S-nitrosothiols derived from nitric oxide and endothelium-derived relaxing factor. Arterioscler. Thromb. 13, 791–799 ( 1993).
  Article CAS Google Scholar
• Qian, H.S., Neplioueva, V., Shetty, G.A., Channon, K.M. & George, S.E. Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits. Circulation 99, 2979–2982 (1999).
  Article CAS Google Scholar
• von der Leyen, H.E. et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc. Natl. Acad. Sci. USA 92, 1137– 1141 (1995).
  Article CAS Google Scholar
• Guo, K., Andrés, V. & Walsh, K. Nitric oxide-induced downregulation of cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells. Circulation 20, 2066–2072 (1998).
  Article Google Scholar
• Laufs, U. & Liao, J.K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J. Biol. Chem. 273, 24266–24271 (1998).
  Article CAS Google Scholar
• Kaesemeyer, W.H., Caldwell, R.B., Huang, J. & Caldwell, R.W. Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. J. Amer. Coll. Cardiol. 33, 234–241 (1999).
  Article CAS Google Scholar
• TASCWorkingGroup. Investigation of patients with intermittent claudication. J. Vasc. Surg. 31 ( Suppl.), S62–S66 (2000).