Der LOX-1-Rezeptor als neues Zielmolekül bei endothelialer Dysfunktion und Atherosklerose

Zusammenfassung

Die Atherosklerose ist mit ihren Komplikationen wie Herzinfarkt und Apoplex die häufigste Todesursache in den Industrieländern. Oxidiertes Low-Density-Lipoprotein spielt eine wichtige Rolle in der Pathogenese der Atherosklerose. Die Hemmung der Cholesterin-Synthese durch Statine hat zahlreiche protektive Wirkungen, kann allein aber die Aufnahme von oxidiertem LDL und die Ausbildung atherosklerotischer Plaques nicht verhindern. Vor diesem Hintergrund ist eine selektive pharmakologische Hemmung der Aufnahme von oxidiertem LDL in Endothelzellen ein interessanter therapeutischer Ansatz. Ein wichtiges neues Zielmolekül ist der endotheliale Lectin-like oxLDL-Rezeptor LOX-1. Der LOX-1-Rezeptor kann minimal und hoch oxidiertes LDL aufnehmen. Außerdem vermittelt er die endotheliale Phagozytose alternder und apoptotischer Zellen, spielt eine Rolle bei der Thrombozytenadhäsion und bei der Interaktion zwischen bakteriellen Proteinen und Endothelzellen in der Sepsis. LOX-1 wird durch proinflammatorische Zytokine, oxLDL, Angiotensin II, Endothelin-1 und arterielle Hypertonie aktiviert. Durch die endotheliale oxLDL-Aufnahme verstärkt LOX-1 die endotheliale Dysfunktion und die Atherosklerose. Daher wird LOX-1 als ein neues Bindeglied zwischen Hypertonie und Atherosklerose angesehen. Transgene Überexpression des LOX-1-Rezeptors induziert bei fettreicher Diät eine intramyokardiale Vaskulopathie und eine eingeschränkte Endothelfunktion in den Widerstandsgefäßen. Genetische Deletion des LOX-1-Gens reduziert dagegen die Ausbildung von atherosklerotischen Plaques. Klinisch wird der LOX-1-Rezeptor in der Frühphase der endothelialen Dysfunktion und der Atherogenese in arteriellen Gefäßen von Patienten mit koronarer Herzkrankheit nachgewiesen. Zahlreiche neue Befunde unterstützen eine Rolle von LOX-1 in der endothelialen Dysfunktion bei diabetischer Vaskulopathie und Nephropathie, Hypercholesterinämie, Adipositas und Präeklampsie. Der LOX-1-Rezeptor ist damit ein neues interessantes Zielmolekül bei endothelialer Dysfunktion und Atherosklerose.

Abstract

Atherosclerosis with its complications like heart attack and stroke, is the most frequent cause of death in the industrialized countries. Oxidized low-density lipoproteins (LDL) play a major role in the pathogenesis of atherosclerosis. Inhibition of cholesterol synthesis by statins has several protective effects but is not sufficient to prevent the uptake of oxidized LDL and the development of atherosclerotic plaques. For this reason a selective pharmacological inhibition of the uptake of oxidized LDL (oxLDL) in endothelial cells is an interesting therapeutic approach. An important novel target molecule is the endothelial lectin-like oxLDL receptor LOX-1. This receptor is able to take up both minimally and highly oxidized LDL. In addition it mediates endothelial phagocytosis of aged and apoptotic cells and plays a role in thrombocyte adhesion and in the interaction between bacterial proteins and endothelial cells in sepsis. LOX-1 is induced by proinflammatory cytokines, oxLDL, angiotensin II, endothelin-1 and arterial hypertension. LOX-1 increases endothelial dysfunction and atherosclerosis by endothelial uptake of oxLDL. This is the reason why LOX-1 has been considered as a novel link between hypertension and atherosclerosis. Transgenic overexpression of the LOX-1 receptor and high-fat diet induces intramyocardial vascular disease and endothelial dysfunction in resistance arteries. In contrast, genetic deletion of the LOX-1 gene reduces the development of atherosclerotic plaques. In the clinical context LOX-1 has been detected in the early phase of endothelial dysfunction and atherosclerosis in arteries of patients with coronary heart disease. Several novel data support a role of LOX-1 in the endothelial dysfunction in diabetic vascular and renal disease, hypercholesterolemia, obesity and preeclampsia. This makes the LOX-1 receptor a novel and interesting target molecule in endothelial dysfunction and atherosclerosis.

Schlüsselwörter

Atherosklerose - endotheliale Dysfunktion - Low-Density-Lipoprotein - LOX-1 - Statine

Keywords

atherosclerosis - endothelial dysfunction - low-density lipoprotein - LOX-1 - statins

Literatur

• 1 4S-Group . Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;  344 1383-1389
• 2 Brinkley T E, Kume N, Mitsuoka H, Phares D A, Hagberg J M. Elevated soluble lectin-like oxidized LDL receptor-1 (sLOX-1) levels in obese postmenopausal women.  Obesity (Silver Spring). 2008;  16 1454-1456
• 3 Brown G, Albers J J, Fisher L D. et al . Regression of coronary artery disease as a result of intensive lipid- lowering therapy in men with high levels of apolipoprotein B.  N Engl J Med. 1990;  323 1289-1298
• 4 Chen H, Li D, Sawamura T, Inoue K, Mehta J L. Upregulation of LOX-1 expression in aorta of hypercholesterolemic rabbits: modulation by losartan.  Biochem Biophys Res Commun. 2000;  276 1100-1104
• 5 Chen M, Masaki T, Sawamura T. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis.  Pharmacol Ther. 2002;  95 89-100
• 6 Chen M, Nagase M, Fujita T, Narumiya S, Masaki T, Sawamura T. Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and AGE.  Biochem Biophys Res Commun. 2001;  287 962-968
• 7 Chen X, Zhang T, Du G. Advanced glycation end products serve as ligands for lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): biochemical and binding characterizations assay.  Cell Biochem Funct. 2008;  26 760-770
• 8 Eichhorn B, Muller G, Leuner A, Sawamura T, Ravens U, Morawietz H. Impaired vascular function in small resistance arteries of LOX-1 overexpressing mice on high-fat diet.  Cardiovasc Res. 2009;  82 493-502
• 9 Goette A, Bukowska A, Dobrev D. et al . Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles.  Eur Heart J. 2009;  30 1411-1420
• 10 Hu C, Dandapat A, Sun L. et al . Regulation of TGFbeta1-mediated collagen formation by LOX-1: studies based on forced overexpression of TGFbeta1 in wild-type and lox-1 knock-out mouse cardiac fibroblasts.  J Biol Chem. 2008;  283 10226-10231
• 11 Hu C, Dandapat A, Chen J. et al . LOX-1 deletion alters signals of myocardial remodeling immediately after ischemia-reperfusion.  Cardiovasc Res. 2007;  76 292-302
• 12 Inoue K, Arai Y, Kurihara H, Kita T, Sawamura T. Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice.  Circ Res. 2005;  97 176-184
• 13 Kataoka H, Kume N, Minami M. et al . Expression of lectin-like oxidized LDL receptor-1 in human atherosclerotic lesions.  Ann N Y Acad Sci. 2000;  902 328-335
• 14 Kita T. LOX-1, a possible clue to the missing link between hypertension and atherogenesis.  Circ Res. 1999;  84 1113-1115
• 15 Kobayashi N, Yoshida K, Mita S. et al . Betaxolol stimulates eNOS production associated with LOX-1 and VEGF in Dahl salt-sensitive rats.  J Hypertens. 2004;  22 1397-1402
• 16 Kume N, Murase T, Moriwaki H. et al . Inducible expression of lectin-like oxidized LDL receptor-1 in vascular endothelial cells.  Circ Res. 1998;  83 322-327
• 17 Li L, Sawamura T, Renier G. Glucose enhances endothelial LOX-1 expression: role for LOX-1 in glucose-induced human monocyte adhesion to endothelium.  Diabetes. 2003;  52 1843-1850
• 18 Liao J K. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition beyond low-density lipoprotein cholesterol.  Am J Cardiol. 2005;  96 24F-33F
• 19 Liew T V, Ray K K. Intensive statin therapy in acute coronary syndromes.  Curr Atheroscler Rep. 2008;  10 158-163
• 20 LIPID-Study-Group . 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
• 21 Lusis A J. Atherosclerosis.  Nature. 2000;  407 233-241
• 22 Mehta J L, Li D Y. Identification and autoregulation of receptor for OX-LDL in cultured human coronary artery endothelial cells.  Biochem Biophys Res Commun. 1998;  248 511-514
• 23 Mehta J L, Chen J, Hermonat P L, Romeo F, Novelli G. Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders.  Cardiovasc Res. 2006;  69 36-45
• 24 Mehta J L, Sanada N, Hu C P. et al . Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet.  Circ Res. 2007;  100 1634-1642
• 25 Morawietz H. LOX-1 and atherosclerosis: proof of concept in LOX-1-knockout mice.  Circ Res. 2007;  100 1534-1536
• 26 Morawietz H, Duerrschmidt N, Niemann B, Galle J, Sawamura T, Holtz J. Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells.  Biochem Biophys Res Commun. 2001;  284 961-965
• 27 Morawietz H, Rueckschloss U, Niemann B. et al . Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein.  Circulation. 1999;  100 899-902
• 28 Morawietz H, Erbs S, Holtz J. et al . Endothelial Protection, AT1 blockade and Cholesterol-Dependent Oxidative Stress: the EPAS trial.  Circulation. 2006;  114 I296-301
• 29 Muller G, Morawietz H. Nitric Oxide, NAD(P)H Oxidase and Atherosclerosis.  Antioxid Redox Signal. 2009;  11 1711-1731
• 30 Muller G, Morawietz H. NAD(P)H oxidase and endothelial dysfunction.  Horm Metab Res. 2009;  41 152-158
• 31 Murase T, Kume N, Kataoka H. et al . Identification of soluble forms of lectin-like oxidized LDL receptor-1.  Arterioscler Thromb Vasc Biol. 2000;  20 715-720
• 32 Nagase M, Hirose S, Sawamura T, Masaki T, Fujita T. Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats.  Biochem Biophys Res Commun. 1997;  237 496-498
• 33 Oka K, Sawamura T, Kikuta K. et al . Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells.  Proc Natl Acad Sci USA. 1998;  95 9535-9540
• 34 Puccetti L, Sawamura T, Pasqui A L, Pastorelli M, Auteri A, Bruni F. Atorvastatin reduces platelet-oxidized-LDL receptor expression in hypercholesterolaemic patients.  Eur J Clin Invest. 2005;  35 47-51
• 35 Renie G, Maingrette F, Li L. Diabetic vasculopathy and the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1).  Curr Diabetes Rev. 2007;  3 103-110
• 36 Rosenblat M, Aviram M. Paraoxonases role in the prevention of cardiovascular diseases.  Biofactors. 2009;  35 98-104
• 37 Rubba P. Effects of atorvastatin on the different phases of atherogenesis.  Drugs. 2007;  67 Suppl 1 17-27
• 38 Rueckschloss U, Quinn M T, Holtz J, Morawietz H. Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease.  Arterioscler Thromb Vasc Biol. 2002;  22 1845-1851
• 39 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
• 40 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
• 41 Sankaralingam S, Xu Y, Sawamura T, Davidge S T. Increased lectin-like oxidized low-density lipoprotein receptor-1 expression in the maternal vasculature of women with preeclampsia: role for peroxynitrite.  Hypertension. 2009;  53 270-277
• 42 Sawamura T, Kume N, Aoyama T. et al . An endothelial receptor for oxidized low-density lipoprotein.  Nature. 1997;  386 73-77
• 43 Shashkin P, Dragulev B, Ley K. Macrophage differentiation to foam cells.  Curr Pharm Des. 2005;  11 3061-3072
• 44 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
• 45 Shiu S W, Tan K C, Wong Y, Leng L, Bucala R. Glycoxidized LDL increases lectin-like oxidized low density lipoprotein receptor-1 in diabetes mellitus.  Atherosclerosis. 2009;  203 522-527
• 46 Tan K C, Shiu S W, Wong Y, Leng L, Bucala R. Soluble lectin-like oxidized low density lipoprotein receptor-1 in type 2 diabetes mellitus.  J Lipid Res. 2008;  49 1438-1444
• 47 Tanigawa H, Miura S, Zhang B. et al . Low-density lipoprotein oxidized to various degrees activates ERK1/2 through Lox-1.  Atherosclerosis. 2006;  188 245-250
• 48 Xie Q, Matsunaga S, Niimi S. et al . Human lectin-like oxidized low-density lipoprotein receptor-1 functions as a dimer in living cells.  DNA Cell Biol. 2004;  23 111-117
• 49 Yamamoto N, Toyoda M, Abe M. et al . Lectin-like oxidized LDL receptor-1 (LOX-1) expression in the tubulointerstitial area likely plays an important role in human diabetic nephropathy.  Intern Med. 2009;  48 189-194