Do pleiotropic effects of statins beyond lipid alterations exist in vivo? What are they and how do they differ between statins?

Current Atherosclerosis Reports

Volumn 2, Issue 1, 2000, Pages 20-25

  Faggiotto, Agostino ^a   Paoletti, Rodolfo ^a  

^a UNIVERSITY OF MILAN   (Italy)

Author keywords

Lovastatin; Pleiotropic Effect; Pravastatin; Simvastatin; Statin

Indexed keywords

ANTIOXIDANT; HYPOCHOLESTEROLEMIC AGENT;

ARTERIOSCLEROSIS; ENDOTHELIUM; HUMAN; INFLAMMATION; LIPID METABOLISM; PHYSIOLOGY; REVIEW; THROMBOCYTE;

ANTICHOLESTEREMIC AGENTS; ANTIOXIDANTS; ARTERIOSCLEROSIS; BLOOD PLATELETS; ENDOTHELIUM; HUMANS; INFLAMMATION; LIPID METABOLISM;

EID: 0033730574     PISSN: 15233804     EISSN: 15346242     Source Type: Journal    
DOI: 10.1007/s11883-000-0091-3     Document Type: Article

References (58)

1. Shepherd J, Cobbe SM, Ford I, et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West Of Scotland Coronary Prevention Study Group. N Engl J Med 1995, 333:1301–1307. DOI: 10.1056/NEJM199511163332001
2. Sacks FM, Pfeffer MA, Moye LA, et al.: The effect of pravastatin on coronary events after myocardial infarction in patient with average cholesterol levels. N Engl J Med 1996, 335:1001–1009. DOI: 10.1056/NEJM199610033351401
3. Downs JR, Clearfield M, Weis S, et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA 1998, 279:1615–1622. DOI: 10.1001/jama.279.20.1615
4. Buchwald H, Campos CT, Boen JR: Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholesterolemia: report from the program on the surgical control of the hyperlipidemias (POSCH). J Am Coll Cardiol 1995, 26:351–357. DOI: 10.1016/0735-1097(95)80006-3
5. Lipid Research Clinic Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results: 1. Reduction in incidence of coronary heart disease. JAMA 1984, 251:351–364. DOI: 10.1001/jama.251.3.351
6. Laufs U, La Fata V, Plutzky J, et al.: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 97:1129–135.
7. Brandes RP, Behra A, Lebherz C, et al.: Lovastatin maintains nitric oxide—but not EDHF-mediated endothelium-dependent relaxation in the hypercholesterolemic rabbit carotid artery. Atherosclerosis 1999, 142:97–104. DOI: 10.1016/S0021-9150(98)00197-X
8. Endres M, Laufs U, Huang Z, et al.: Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. PNA S 1998, 95:8880–8885. DOI: 10.1073/pnas.95.15.8880
9. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al.: Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998, 101:2711–2719. DOI: 10.1172/JCI1500
10. Essig M, Nguyen G, Prie D, et al.: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ Res 1998, 83:683–690.
11. Bellosta S, Bernini F, Ferri N, et al.: Direct vascular effects of HMG-CoA reductase inhibitors. Atherosclerosis. 1998, 137:S101-S109. DOI: 10.1016/S0021-9150(97)00319-5
12. Colli S, Eligini S, Lalli M, et al.: Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arter Thromb Vasc Biol 1997, 17:265–272.
13. Muller C, Kiehl MG, van de Loo J, et al.: Lovastatin induces p21WAF1/Cip1 in human vascular smooth muscle cells: influence on protein phosphorylation, cell cycle, induction of apoptosis, and growth inhibition. Bioorg Med Chem Letters 1999, 3:63–68.
14. Corsini A, Bernini F, Quarato P, et al.: Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Cardiology 1996, 87:458–468. DOI: 10.1159/000177139
15. Vrtovsnik F, Couette S, Prie D, et al.: Lovastatin-induced inhibition of renal epithelial tubular cell proliferation involves a p21ras activated, AP-1-dependent pathway. Kidney Int 1997, 52:1016–1027. DOI: 10.1038/ki.1997.423
16. Nakagawa H, Mutoh T, Kumano T, et al.: HMG-CoA reductase inhibitor-induced L6 myoblast cell death: involvement of the phosphatidylinositol 3-kinase pathway. FEBS Letters 1998, 438:289–292. DOI: 10.1016/S0014-5793(98)01320-9
17. Jiang J, Roman RJ: Lovastatin prevents development of hypertension in spontaneously hypertensive rats. Hypertension 1997, 30:968–974.
18. Mitani H, Bandoh T, Ishikawa J, et al.: Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits. Br J Pharmacol. 1996, 119:1269–1275.
19. Sposito AC, Mansur AP, Coelho OR, et al.: Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors (Enalapril or Lisinopril). Am J Cardiol 1999, 83:1497–1499. DOI: 10.1016/S0002-9149(99)00132-0
20. Farnier M, Davignon J: Current and future treatment of hyperlipidemia: the role of statins. Am J Cardiol 1998, 82:J3-J10. DOI: 10.1016/S0002-9149(98)00423-8
21. Corsini A, Bellosta S, Baetta R, et al.: New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999, in press.
22. Kreuzer J, Bader J, Jahn L, et al.: Chemotaxis of the monocyte cell line U937: dependence on cholesterol and early mevalonate pathway products. Atherosclerosis 1991, 90:203–209. DOI: 10.1016/0021-9150(91)90116-K
23. Rudich SM, Mongini PK, Perez RV, et al.: HMG-CoA reductase inhibitors pravastatin and simvastatin inhibit human B-lymphocyte activation. Transpl Proc 1998, 30:992–995. DOI: 10.1016/S0041-1345(98)00123-7
24. Muldoon MF, Flory JD, Marsland A, et al.: Effects of lovastatin on the immune system. Am J Cardiol 1997, 80:1391–1394. DOI: 10.1016/S0002-9149(97)00695-4
25. Katznelson S, Wang XM, Chia D, et al.: The inhibitory effects of pravastatin on natural killer cell activity in vivo and on cytotoxic T lymphocyte activity in vitro. J Heart Lung Transplant 1998, 17:335–340.
26. Kobashigawa JA, Katznelson S, Laks H, et al.: Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995, 333:621–627. DOI: 10.1056/NEJM199509073331003
27. Bellosta S, Via D, Canavesi M, et al.: HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscl Thromb Vasc Biol. 1998, 18:1671–1678.
28. Giroux LM, Davignon J, Naruszewicz M: Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. BBA 1993, 1165:335–338.
29. Fisher JE, Rogers MJ, Halasy JM, et al.: Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. PNAS (USA) 1999, 96:133–138. DOI: 10.1073/pnas.96.1.133
30. Gujarro C, Blanco-Colio LM, Ortego M, et al.: 3-hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 1998, 83:490–500.
31. Dimitroulakos J, Nohynek D, Backway KL, et al.: Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach. Blood 1999, 93:1308–18.
32. Tan A, Levrey H, Dahm C, et al.: Lovastatin induces fibroblast apoptosis in vitro and in vivo. A possible therapy for fibroproliferative disorders. Am J Resp & Crit Care Med. 1999, 159:220–227.
33. Shipman CM, Croucher PI, Russell RG, et al.: The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res 1998, 58:5294–5297.
34. Rao S, Lowe M, Herliczek TW, et al.: Lovastatin mediated G1 arrest in normal and tumor breast cells is through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53. Oncogene 1998, 17:2393–2402. DOI: 10.1038/sj.onc.1202322
35. Rubins JB, Greatens T, Kratzke RA, et al.: Lovastatin induces apoptosis in malignant mesothelioma cells. Am J Resp Crit Care Med 1998, 157:1616–1622.
36. Crick DC, Andres DA, Danesi R, et al.: Geranylgeraniol overcomes the block of cell proliferation by lovastatin in C6 glioma cells.
37. Lee SJ, Ha MJ, Lee J, et al.: Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21 (WAF1/CIP1) in human prostate carcinoma cells. J Biol Chem 1998, 273:10618–10623. DOI: 10.1074/jbc.273.17.10618
38. Marcelli M, Cunningham GR, Haidacher SJ, et al.: Caspase-7 is activated during lovastatin-induced apoptosis of the prostate cancer cell line LNCaP. Cancer Res 1998, 58:76–83.
39. Muller C, Bockhorn AG, Klusmeier S, et al.: Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis. Int J Oncol 1998, 12:717–723.
40. Hunakova L, Sedlak J, Sulikova M, et al.: Human multidrug-resistant (MRP,p190) myeloid leukemia HL-60/ADR cells in vitro: resistance to the mevalonate pathway inhibitor lovastatin. Neoplasma 1997, 44:366–369.
41. Ghosh PM, Mott GE, Ghosh-Choudhury N, et al.: Lovastatin induces apoptosis by inhibiting mitotic and post-mitotic events in cultured mesangial cells. Biochem Biophys Acta 1997, 1359:13–24. DOI: 10.1016/S0167-4889(97)00091-8
42. Cui Q, Wang GJ, Su CC, et al.: The Otto Aufranc Award. Lovastatin prevents steroid induced adipogenesis and osteonecrosis. Clin Orthop Rel Res 1997, 344:8–19.
43. Soma MR, Baetta R, De Renzis MR, et al.: In vivo enhanced antitumor activity of carmustine [N,N′-bis(2-chloroethyl)-N-nitrosourea] by simvastatin. Cancer Res 1995, 55:597–602.
44. Melichar B, Ferrandina G, Verschraegen CF, et al.: Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines. Clin Cancer Res 1998, 4:3069–3076.
45. Scandinavian Simvastatin Survival Group. Randomized trial of cholesterol lowering in 4444 patients with coronary disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344:1383–1389. DOI: 10.1016/S0140-6736(94)90566-5
46. MacMahon S, Sharpe N, Gamble G, et al.: Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID. Circulation 1997, 97:1784–1790.
47. Corsini A, Pazzucconi F, Pfister P, et al.: Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin. Lancet 1996, 348:1584. DOI: 10.1016/S0140-6736(05)66196-X
48. Tsuda Y, Satoh K, Kitadai M, et al.: Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia. Atherosclerosis. 1996, 22:225–233. DOI: 10.1016/0021-9150(95)05757-9
49. Kohno M, Murakawa K, Yasunari K, et al.: Improvement of erythrocyte deformability by cholesterol-lowering therapy with pravastatin in hypercholesterolemic patients. Metabolism 1997, 46:287–291. DOI: 10.1016/S0026-0495(97)90255-9
50. Mercuri M, Bond MG, Sirtori CR, et al.: Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranean population: The Carotid Atherosclerosis Italian Ultrasound Study. Am J Med 1996, 101:627–634. DOI: 10.1016/S0002-9343(96)00333-6
51. Aviram M, Hussein O, Rosenblat M, et al.: Interactions of platelets, macrophages, and lipoproteins in hypercholesterolemia: antiatherogenic effects of HMG-CoA reductase inhibitor therapy. J Cardiol Pharmacol 1998, 31:39–45. DOI: 10.1097/00005344-199801000-00006
52. Gould KL, Martucci JP, Goldberg DI, et al.: Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium. Circulation 1994, 89:1530–1538.
53. Prospective Studies Collaboration: Cholesterol, diastolic blood pressure, and stroke, 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995, 346:1647–1653. DOI: 10.1016/S0140-6736(95)92836-7
54. Thibault A, Samid D, Tompkins AC, et al.: Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 1996, 2:483–491.
55. Larner J, Jane J, Laws E, et al.: A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme. Am J Clin Oncol 1998, 21:579–583. DOI: 10.1097/00000421-199812000-00010
56. Hamelin BA, Turgeon J: Hydrophilicity/lipophilicitity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. TiPS. 1998, 19:26–37.
57. Newby AC, Libby P, van der Wal AC. Plaque instability—the real challenge for atherosclerosis research in the next decade? Cardiovasc Res 1999, 41:321–322. DOI: 10.1016/S0008-6363(98)00286-7
58. Libby P, Aikawa M: New insights into plaque stabilisation by lipid lowering. Drugs 1998, 56(Suppl 1):9–13. DOI: 10.2165/00003495-199856001-00002