Effects of Statins on Endothelium and Endothelial Progenitor Cell Recruitment

Dirk H. Walter; Stefanie Dimmeler; Andreas M. Zeiher

doi:10.1055/s-2004-869595

Seminars in Vascular Medicine, Inhaltsverzeichnis

Semin Vasc Med 2004; 4(4): 385-393
DOI: 10.1055/s-2004-869595

Effects of Statins on Endothelium and Endothelial Progenitor Cell Recruitment

Dirk H. Walter¹ , Stefanie Dimmeler¹ , Andreas M. Zeiher¹

¹Department of Internal Medicine IV, Division of Cardiology and Molecular Cardiology, University of Frankfurt, Frankfurt, Germany

Abstract

ABSTRACT

Statins appear to be potent drugs with a variety of pleiotropic effects with vasculoprotective and cardioprotective activity. The beneficial effects of statins on endothelial cells as well as on endothelial cell function appear to be related to improved nitric oxide bioavailability. Mechanistically, statins induce endothelial nitric oxide synthase mRNA stability in endothelial cells and promote endothelial nitric oxide synthase activity through a PI3K/Akt dependent pathway, which is a common signal transduction pathway shared by growth factors such as vascular endothelial growth factors or fibroblast growth factors (FGFs), estrogens, or statins. Furthermore, statins have potent antiinflammatory capacities by potently interfering with the generation of reactive oxygen species or activating scavenging systems for free radicals such as the thioredoxin system. These mechanisms might all contribute to improved NO bioavailability and confer the beneficial actions of statins. The proangiogenic properties of statins and their effects on reendothelialization following vessel injury include novel actions such as the mobilization, differentiation, and improved survival of endothelial progenitor cells. Statin therapy might reverse the impaired functional regeneration capacities seen in patients with risk factors for coronary artery disease or documented active coronary artery disease by specifically interacting with progenitor cell function. Accordingly, augmentation of functionally active endothelial progenitor cells with improved homing capacity will be a critical step in advancing therapeutic neovascularization as well as reendothelialization in patients with coronary artery disease.

KEYWORDS

Statins - progenitor cells - endothelium - coronary artery disease

Volltext

Referenzen

REFERENCES

1 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) . Lancet. 1994; 344 1383-1389
2 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels . The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998; 339 1349-1357
3 Sacks F M, Pfeffer M A, Moye L A 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. 1996; 335 1001-1009
4 Maron D J, Fazio S, Linton M F. Current perspectives on statins. Circulation. 2000; 101 207-213
5 Shepherd J, Cobbe S M, 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
6 Downs J R, 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. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998; 279 1615-1622
7 Grundy S M. Statin trials and goals of cholesterol-lowering therapy. Circulation. 1998; 97 1436-1439
8 Heart Protection Study Collaborative Group . MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360 7-22
9 Laufs U, Liao J K. Rapid effects of statins: from prophylaxis to therapy for ischemic stroke. Arterioscler Thromb Vasc Biol. 2003; 23 156-157
10 Wierzbicki A S, Reynolds T M. Statins and fractures. Lancet. 2001; 357 1887-1889
11 Ikeda Y, Young L H, Lefer A M. Rosuvastatin, a new HMG-CoA reductase inhibitor, protects ischemic reperfused myocardium in normocholesterolemic rats. J Cardiovasc Pharmacol. 2003; 41 649-656
12 Wolfrum S, Grimm M, Heidbreder M et al.. Acute reduction of myocardial infarct size by a hydroxymethyl glutaryl coenzyme A reductase inhibitor is mediated by endothelial nitric oxide synthase. J Cardiovasc Pharmacol. 2003; 41 474-480
13 Rivard A, Fabre J E, Silver M et al.. Age-dependent impairment of angiogenesis. Circulation. 1999; 99 111-120
14 Rivard A, Silver M, Chen D et al.. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol. 1999; 154 355-363
15 Isner J M, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest. 1999; 103 1231-1236
16 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 1004-1010
17 Zbinden S, Brunner N, Wustmann K, Billinger M, Meier B, Seiler C. Effect of statin treatment on coronary collateral flow in patients with coronary artery disease. Heart. 2004; 90 448-449
18 Sata M, Nishimatsu H, Suzuki E et al.. Endothelial nitric oxide synthase is essential for the HMG-CoA reductase inhibitor cerivastatin to promote collateral growth in response to ischemia. FASEB J. 2001; 15 2530-2532
19 Dupuis J, Tardif J C, 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 3227-3233
20 Treasure C B, Klein J L, Weintraub W S et al.. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995; 332 481-487
21 Vita J A, Yeung A C, Winniford M et al.. Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease. Circulation. 2000; 102 846-851
22 Asahara T, Murohara T, Sullivan A et al.. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275 964-967
23 Asahara T, Masuda H, Takahashi T et al.. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999; 85 221-228
24 Rosenson R S, Tangney C C. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA. 1998; 279 1643-1650
25 Schachinger V, Britten M B, Zeiher A M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000; 101 1899-1906
26 Halcox J P, Schenke W H, Zalos G et al.. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002; 106 653-658
27 Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003; 108 2093-2098
28 Balletshofer B M, Rittig K, Enderle M D et al.. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation. 2000; 101 1780-1784
29 Schachinger V, Britten M B, Elsner M, Walter D H, Scharrer I, Zeiher A M. A positive family history of premature coronary artery disease is associated with impaired endothelium-dependent coronary blood flow regulation. Circulation. 1999; 100 1502-1508
30 Wolfrum S, Jensen K S, Liao J K. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol. 2003; 23 729-736
31 Heeschen C, Hamm C W, Laufs U, Bohm M, Snapinn S, White H D. Withdrawal of statins in patients with acute coronary syndromes. Circulation. 2002; 105 1446-1452
32 Laufs U, Endres M, Custodis F et al.. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of Rho GTPase gene transcription. Circulation. 2000; 102 3104-3110
33 Lefer A M, Lefer D J. The role of nitric oxide and cell adhesion molecules on the microcirculation in ischaemia-reperfusion. Cardiovasc Res. 1996; 32 743-751
34 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
35 Laufs U, Liao J K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998; 273 24266-24271
36 Dimmeler S, Fisslthaler B, Fleming I, Hermann C, Busse R, Zeiher A M. Activation of nitric oxide synthase in endothelial cells via Akt-dependent phosphorylation. Nature. 1999; 399 601-605
37 Fulton D, Gratton J P, McCabe T J et al.. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999; 399 597-601
38 Haendeler J, Hoffmann J, Zeiher A M, Dimmeler S. Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells: a novel vasculoprotective function of statins. Circulation. 2004; 110 856-861
39 Haendeler J, Hoffmann J, Tischler V, Berk B C, Zeiher A M, Dimmeler S. Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nat Cell Biol. 2002; 4 743-749
40 Shishehbor M H, Brennan M L, Aviles R J et al.. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation. 2003; 108 426-431
41 Rueckschloss U, Galle J, Holtz J, Zerkowski H R, Morawietz H. Induction of NAD(P)H oxidase by oxidized low-density lipoprotein in human endothelial cells: antioxidative potential of hydroxymethylglutaryl coenzyme A reductase inhibitor therapy. Circulation. 2001; 104 1767-1772
42 Wassmann S, Laufs U, Muller K et al.. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2002; 22 300-305
43 Takemoto M, Node K, Nakagami H et al.. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest. 2001; 108 1429-1437
44 Plenge J K, Hernandez T L, Weil K M et al.. Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction. Circulation. 2002; 106 1447-1452
45 Rezaie-Majd A, Maca T, Bucek R A et al.. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2002; 22 1194-1199
46 Rezaie-Majd A, Prager G W, Bucek R A et al.. Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2003; 23 397-403
47 Weitz-Schmidt G, Welzenbach K, Brinkmann V et al.. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med. 2001; 7 687-692
48 Takeshita S, Zheng L P, Brogi E et al.. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest. 1994; 93 662-670
49 Meurice T, Bauters C, Auffray J L et al.. Basic fibroblast growth factor restores endothelium-dependent responses after balloon injury of rabbit arteries. Circulation. 1996; 93 18-22
50 Pare G, Krust A, Karas R H et al.. Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res. 2002; 90 1087-1092
51 Krasinski K, Spyridopoulos I, Asahara T, van der Zee R, Isner J M, Losordo D W. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation. 1997; 95 1768-1772
52 Mendelsohn M E, Karas R H. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999; 340 1801-1811
53 Skaletz-Rorowski A, Lutchman M, Kureishi Y, Lefer D J, Faust J R, Walsh K. HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. Cardiovasc Res. 2003; 57 253-264
54 Morales-Ruiz M, Fulton D, Sowa G et al.. Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. Circ Res. 2000; 86 892-896
55 Urbich C, Dernbach E, Zeiher A M, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res. 2002; 90 737-744
56 Weis M, Heeschen C, Glassford A J, Cooke J P. Statins have biphasic effects on angiogenesis. Circulation. 2002; 105 739-745
57 Eto M, Kozai T, Cosentino F, Joch H, Luscher T F. Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation. 2002; 105 1756-1759
58 Laufs U, Kilter H, Konkol C, Wassmann S, Bohm M, Nickenig G. Impact of HMG CoA reductase inhibition on small GTPases in the heart. Cardiovasc Res. 2002; 53 911-920
59 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000; 6 389-395
60 Assmus B, Schachinger V, Teupe C et al.. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002; 106 3009-3017
61 Strauer B E, Brehm M, Zeus T et al.. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002; 106 1913-1918
62 Perin E C, Dohmann H F, Borojevic R et al.. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003; 107 2294-2302
63 Shi Q, Rafii S, Wu M H et al.. Evidence for circulating bone marrow-derived endothelial cells. Blood. 1998; 92 362-367
64 Bhattacharya V, McSweeney P A, Shi Q et al.. Enhanced endothelialization and microvessel formation in polyester grafts seeded with CD34(+) bone marrow cells. Blood. 2000; 95 581-585
65 Peichev M, Naiyer A J, Pereira D et al.. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000; 95 952-958
66 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; 108 391-397
67 Murohara T, Ikeda H, Duan J et al.. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest. 2000; 105 1527-1536
68 Schatteman G C, Hanlon H D, Jiao C, Dodds S G, Christy B A. Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest. 2000; 106 571-578
69 Vasa M, Fichtlscherer S, Aicher A et al.. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001; 89 E1-E7
70 Kalka C, Masuda H, Takahashi T et al.. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000; 97 3422-3427
71 Blau H M, Brazelton T R, Weimann J M. The evolving concept of a stem cell: entity or function?. Cell. 2001; 105 829-841
72 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
73 Vasa M, Fichtlscherer S, Adler K et al.. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001; 103 2885-2890
74 Kalka C, Masuda H, Takahashi T et al.. Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res. 2000; 86 1198-1202
75 Walter D H, Rittig K, Bahlmann F H et al.. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation. 2002; 105 3017-3024
76 Werner N, Priller J, Laufs U et al.. Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol. 2002; 22 1567-1572
77 Friedlander M, Brooks P C, Shaffer R W, Kincaid C M, Varner J A, Cheresh D A. Definition of two angiogenic pathways by distinct alphav integrins. Science. 1995; 270 1500-1502
78 Eliceiri B P, Cheresh D A. The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest. 1999; 103 1227-1230
79 Indolfi C, Cioppa A, Stabile E et al.. Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol. 2000; 35 214-221
80 Walter D H, Schachinger V, Elsner M, Mach S, Auch-Schwelk W, Zeiher A M. Effect of statin therapy on restenosis after coronary stent implantation. Am J Cardiol. 2000; 85 962-968
81 Van Belle E, Tio F O, Chen D, Maillard L, Kearney M, Isner J M. Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol. 1997; 29 1371-1379
82 Asahara T, Chen D, Tsurumi Y et al.. Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer. Circulation. 1996; 94 3291-3302
83 Iwakura A, Luedemann C, Shastry S et al.. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation. 2003; 108 3115-3121
84 Cho H J, Kim H S, Lee M M et al.. Mobilized endothelial progenitor cells by granulocyte-macrophage colony-stimulating factor accelerate reendothelialization and reduce vascular inflammation after intravascular radiation. Circulation. 2003; 108 2918-2925
85 Gulati R, Jevremovic D, Peterson T E et al.. Autologous culture-modified mononuclear cells confer vascular protection after arterial injury. Circulation. 2003; 108 1520-1526
86 Werner N, Junk S, Laufs U et al.. Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res. 2003; 93 e17-e24
87 Griese D P, Ehsan A, Melo L G et al.. Isolation and transplantation of autologous circulating endothelial cells into denuded vessels and prosthetic grafts: implications for cell-based vascular therapy. Circulation. 2003; 108 2710-2715
88 Fujiyama S, Amano K, Uehira K et al.. Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells. Circ Res. 2003; 93 980-989
89 Heeschen C, Lehmann R, Honold J et al.. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation. 2004; 109 1615-1622
90 Gennaro G, Menard C, Michaud S E, Rivard A. Age-dependent impairment of reendothelialization after arterial injury: role of vascular endothelial growth factor. Circulation. 2003; 107 230-233
91 Edelberg J M, Tang L, Hattori K, Lyden D, Rafii S. Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiogenic function. Circ Res. 2002; 90 E89-E93
92 Tepper O M, Galiano R D, Capla J M et al.. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002; 106 2781-2786
93 Hill J M, Zalos G, Halcox J P et al.. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003; 348 593-600
94 Aicher A, Heeschen C, Mildner-Rihm C et al.. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003; 9 1370-1376
95 Assmus B, Urbich C, Aicher A et al.. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res. 2003; 92 1049-1055
96 Badorff C, Popp R, Urbich C et al.. Human adult endothelial progenitor cells transdifferentiate into functionally active cardiac myocytes-essential role of cell-to-cell contact. Circulation. 2003; 107 1024-1032
97 Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodelling. Nature. 2002; 415 240-243
98 Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003; 422 901-904
99 Rupp S, Badorff C, Koyanagi M et al.. Statin therapy in patients with coronary artery disease improves the impaired endothelial progenitor cell differentiation into cardiomyogenic cells. Basic Res Cardiol. 2004; 99 61-68

Dirk H WalterM.D.

Department of Internal Medicine IV, Division of Cardiology, University of Frankfurt

Theodor-Stern-Kai 7, 60590 Frankfurt, Germany