Subscribe to RSS
DOI: 10.1055/s-2007-991158
© Georg Thieme Verlag KG Stuttgart · New York
Low-density Lipoproteins Induce the Renin-Angiotensin System and their Receptors in Human Endothelial Cells
Publication History
received 11.12.2006
accepted 23.04.2007
Publication Date:
09 November 2007 (online)
Abstract
Increased levels of low-density lipoproteins are well-established risk factors of endothelial dysfunction and the metabolic syndrome. In this study, we evaluated the effect of native low-density lipoprotein (nLDL) and oxidized LDL (oxLDL) on the expression of genes of the renin-angiotensin system (angiotensin-converting enzyme, ACE; angiotensin II type 1 receptor, AT1) and their receptors (low-density lipoprotein receptor: LDLR; lectin-like oxLDL receptor: LOX-1; toll-like receptor 4: TLR4) in primary cultures of human umbilical vein endothelial cells. ACE and AT1 expressions were significantly increased after stimulation with nLDL and oxLDL. OxLDL receptor LOX-1 showed a maximum induction after 7 hours. Increased LOX-1 protein expression in response to oxLDL could be blocked by a LOX-1-specific antibody. TLR4 expression was increased by nLDL and oxLDL as well. We conclude that LDL and oxLDL can activate the renin-angiotensin system and their receptors LDLR, LOX-1, and TLR4 in human endothelial cells. These data suggest a novel link between hypercholesterolemia and hypertension in patients with the metabolic syndrome.
Key words
endothelial cells - low-density lipoprotein - oxLDL receptor - renin-angiotensin system
References
- 1 Bonora E. The metabolic syndrome and cardiovascular disease. Ann Med. 2006; 38 64-80
- 2 Deedwania P, Barter P, Carmena R, Fruchart JC, Grundy SM, Haffner S, Kastelein JJ, LaRosa JC, Schachner H, Shepherd J, Waters DD. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the treating to new targets study. Lancet. 2006; 368 919-928
- 3 Nickenig G. Should angiotensin II receptor blockers and statins be combined?. Circulation. 2004; 110 1013-1020
- 4 Lusis AJ. Atherosclerosis. Nature. 2000; 407 233-241
- 5 Kjeldsen SE, Julius S. Hypertension mega-trials with cardiovascular end points: effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Am Heart J. 2004; 148 747-754
- 6 Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley W, Teo K. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation. 2001; 103 919-925
- 7 Strawn WB, Chappell MC, Dean RH, Kivlighn S, Ferrario CM. Inhibition of early atherogenesis by losartan in monkeys with diet- induced hypercholesterolemia. Circulation. 2000; 101 1586-1593
- 8 Ferrario CM, Smith R, Levy P, Strawn W. The hypertension-lipid connection: insights into the relation between angiotensin II and cholesterol in atherogenesis. Am J Med Sci. 2002; 323 17-24
- 9 Nickenig G, Sachinidis A, Michaelsen F, Bohm M, Seewald S, Vetter H. Upregulation of vascular angiotensin II receptor gene expression by low- density lipoprotein in vascular smooth muscle cells. Circulation. 1997; 95 473-478
- 10 Nickenig G, Sachinidis A, Seewald S, Bohm M, Vetter H. Influence of oxidized low-density lipoprotein on vascular angiotensin II receptor expression. J Hypertens Suppl. 1997; 15 S27-S30
- 11 Kong WJ, Liu J, Jiang JD. Human low-density lipoprotein receptor gene and its regulation. J Mol Med. 2006; 84 29-36
- 12 Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997; 386 73-77
- 13 Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC, Luthringer D, Xu XP, Rajavashisth TB, Yano J, Kaul S, Arditi M. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation. 2001; 104 3103-3108
- 14 Faure E, Equils O, Sieling PA, Thomas L, Zhang FX, Kirschning CJ, Polentarutti N, Muzio M, Arditi M. Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem. 2000; 275 11058-11063
- 15 Rueckschloss U, Galle J, Holtz J, Zerkowski HR, 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
- 16 Muller G, Catar RA, Niemann B, Barton M, Knels L, Wendel M, Morawietz H. Upregulation of endothelin receptor B in human endothelial cells by low-density lipoproteins. Exp Biol Med (Maywood). 2006; 231 766-771
- 17 Niemann B, Rohrbach S, Catar RA, Muller G, Barton M, Morawietz H. Native and oxidized low-density lipoproteins stimulate endothelin-converting enzyme-1 expression in human endothelial cells. Biochem Biophys Res Commun. 2005; 334 747-753
- 18 Schubert A, Cattaruzza M, Hecker M, Darmer D, Holtz J, Morawietz H. Shear stress-dependent regulation of the human β-tubulin folding cofactor D gene. Circ Res. 2000; 87 1188-1194
- 19 Li D, Singh RM, Liu L, Chen H, Singh BM, Kazzaz N, Mehta JL. Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells. Cardiovasc Res. 2003; 57 238-243
- 20 Li D, Saldeen T, Romeo F, Mehta JL. Oxidized LDL upregulates angiotensin II type 1 receptor expression in cultured human coronary artery endothelial cells: the potential role of transcription factor NF-kappaB. Circulation. 2000; 102 1970-1976
- 21 Ko Y, Glodny B, Stier S, Totzke G, Nickenig G, Dusing R, Sachinidis A, Vetter H. Angiotensin type-1 (AT1) receptor gene expression in primarily cultured human arterial umbilical endothelial cells. Biochem Pharmacol. 1997; 53 417-421
- 22 Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, Zerkowski HR, Sawamura T, Holtz J. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation. 1999; 100 899-902
- 23 Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL. Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res. 1999; 84 1043-1049
- 24 Muller G, Goettsch C, Morawietz H. Oxidative stress and endothelial dysfunction. Hamostaseologie. 2007; 27 5-12
- 25 Dhaliwal BS, Steinbrecher UP. Scavenger receptors and oxidized low density lipoproteins. Clin Chim Acta. 1999; 286 191-205
- 26 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
- 27 Mehta JL, Li DY. Identification and autoregulation of receptor for OX-LDL in cultured human coronary artery endothelial cells. Biochem Biophys Res Commun. 1998; 248 511-514
- 28 Dimmeler S, Haendeler J, Galle J, Zeiher AM. Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases. A mechanistic clue to the ‘response to injury’ hypothesis. Circulation. 1997; 95 1760-1763
- 29 Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci USA. 2004; 101 10679-10684
- 30 Yang QW, Mou L, Lv FL, Wang JZ, Wang L, Zhou HJ, Gao D. Role of Toll-like receptor 4/NF-kappaB pathway in monocyte-endothelial adhesion induced by low shear stress and ox-LDL. Biorheology. 2005; 42 225-236
- 31 Bornstein SR, Schumann RR, Rettori V, MacCann SM, Zacharowski K. Toll-like receptor 2 and Toll-like receptor 4 expression in human adrenals. Horm Metab Res. 2004; 36 470-473
- 32 Bornstein SR, Morawietz H. Toll-like receptors, endocrine stress response, and arteriosclerosis. Arterioscler Thromb Vasc Biol. 2005; 25 e135
- 33 Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm M, Meinertz T, Munzel T. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin- angiotensin system. Circulation. 1999; 99 2027-2033
- 34 Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M. Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation. 1999; 100 2131-2134
- 35 Schjoedt KJ, Jacobsen P, Rossing K, Boomsma F, Parving HH. Dual blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy: the role of aldosterone. Horm Metab Res. 2005; 37 ((Suppl 1)) 4-8
Correspondence
H. MorawietzPhD
University of Technology Dresden
Carl Gustav Carus Medical School
Medical Clinic and Policlinic III
Department of Vascular Endothelium and Microcirculation
Fetscherstrasse 74
01307 Dresden
Germany
Phone: +49/351/458 66 25
Fax: +49/351/458 63 54
Email: Henning.Morawietz@tu-dresden.de