This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morawietz, H. Articles by Holtz, J. Search for Related Content PubMed PubMed Citation Articles by Morawietz, H. Articles by Holtz, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Coronary Artery Disease Hazardous Substances DB LOSARTAN POTASSIUM Related Collections Lipids ACE/Angiotension receptors Pathophysiology Chronic ischemic heart disease Mechanism of atherosclerosis/growth factors

(Circulation. 1999;100:899-902.)
© 1999 American Heart Association, Inc.

Brief Rapid Communication

Angiotensin II Induces LOX-1, the Human Endothelial Receptor for Oxidized Low-Density Lipoprotein

Presented at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-521).

Henning Morawietz, PhD; Uwe Rueckschloss, MS; Bernd Niemann; Nicole Duerrschmidt, MS; Jan Galle, MD; Kavous Hakim, MD; Hans-Reinhard Zerkowski, MD; Tatsuya Sawamura, MD, PhD; Juergen Holtz, MD

From the Institute of Pathophysiology (H.M., U.R., B.N., N.D., J.H.) and the Clinic for Cardio-Thoracic Surgery (K.H., H.-R.Z.), Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany; the Clinic of Internal Medicine, University Wuerzburg, Germany (J.G.); and the Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan (T.S).

Correspondence to Henning Morawietz, PhD, Institute of Pathophysiology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Magdeburger Straße 18, D-06097 Halle, Germany. E-mail henning.morawietz{at}medizin.uni-halle.de

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—Oxidatively modified LDL (oxLDL) plays an important role in the development of atherosclerosis. OxLDL effects, eg, foam cell formation, are mediated in part by the classic scavenger receptor, whereas other effects may involve the recently cloned endothelial oxLDL receptor, LOX-1 (lectinlike oxLDL receptor-1), which is distinct from macrophage scavenger receptors. Because the regulation of LOX-1 must still be defined, we investigated whether LOX-1 is regulated by the potentially proatherosclerotic stimulant angiotensin II (Ang II).

Methods and Results—Using competitive reverse transcription–polymerase chain reaction (RT-PCR), we quantified mRNA expression of LOX-1 in primary cultures of human umbilical vein endothelial cells (HUVECs). After treatment with Ang II for 3 hours (1 nmol/L to 1 µmol/L), LOX-1 mRNA was concentration-dependently induced (from 6.9±1.4 to 23.1±5.5 relative units [RU] by 1 µmol/L Ang II; P<0.05). The angiotensin II type 1 (AT₁) receptor antagonist losartan prevented this induction. Incubation of HUVECs with Ang II (100 nmol/L, 3 hours) induced LOX-1 protein expression (212±21% of control level; P<0.01) and uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled oxLDL (209±17% of control level; P<0.05) by an AT₁-dependent pathway, reaching its maximum after 24 hours (680±89%; P<0.05). In internal mammary artery biopsy samples from patients with or without ACE inhibitor treatment before coronary artery bypass surgery, LOX-1 mRNA was downregulated by ACE inhibition (6.4±2.0 versus 19.3±5.9 RU; n=12 each; P<0.05).

Conclusions—We conclude that LOX-1 is regulated by Ang II in vitro and in vivo, that induction of LOX-1 is mediated by the AT₁ receptor, and that repression of LOX-1 by long-term ACE inhibitor treatment may contribute to the antiatherosclerotic potential of this therapy.

Key Words: angiotensin • atherosclerosis • coronary disease • endothelium • lipoproteins

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Angiotensin II (Ang II) has been suggested to be involved in the development and progression of atherosclerosis and coronary heart disease. Atherosclerosis is characterized by accumulation of intracellular and extracellular lipids, monocyte/macrophage infiltration, foam cell formation, proliferation of vascular smooth muscle cells, and accumulation of connective tissue proteins.¹

Oxidatively modified LDL (oxLDL) is internalized by macrophages via scavenger receptors, leading to foam cell formation as a hallmark in the development of atherosclerosis.² Moreover, oxLDL induces potentially proatherosclerotic effects in endothelial cells. These effects include impairment of endothelial NO formation,³ induction of endothelial expression of adhesion molecules⁴ and smooth muscle growth factors,⁵ induction of superoxide anion formation from vascular tissue,⁶ and apoptosis of endothelial cells.⁷

Recently, a human endothelial receptor that mediates uptake of oxLDL (lectinlike oxLDL receptor-1 [LOX-1]) has been cloned.⁸ This receptor is structurally distinct from scavenger receptors of macrophages and belongs to the C-type lectin family. LOX-1 has been shown to be inducible by tumor necrosis factor- and phorbol 12-myristate 13-acetate,⁹ and it mediates phagocytosis of aged/apoptotic cells in endothelial cells.¹⁰ However, the effect of Ang II on LOX-1 expression is presently unknown.

The purpose of the present study was to examine the influence of Ang II on expression of LOX-1. We tested whether Ang II induces LOX-1 mRNA and protein expression and oxLDL uptake in human endothelial cells. To provide further evidence that the in vitro findings take place in vivo, we analyzed the effect of long-term ACE inhibitor treatment on vascular expression of LOX-1 in patients with coronary heart disease.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Cell Culture
Cell culture reagents and chemicals were purchased from Sigma Chemical Co except when otherwise specified. Primary cultures of human umbilical vein endothelial cells (HUVECs) were isolated with collagenase IV and grown in medium M199 (Life Technologies) supplemented with 20% fetal serum. Confluent cell cultures were incubated with medium containing 0.5% fetal serum for 24 hours and subsequently treated with Ang II (1 nmol/L to 1 µmol/L) or with Ang II (100 nmol/L) and the angiotensin II type 1 (AT₁) receptor antagonist losartan (1 µmol/L, Merck; Sharpe & Dohme).

Patients
Distal remnant specimens of the left internal mammary artery (arteria thoracica interna) obtained after informed consent from 24 patients undergoing elective CABG surgery were used for this study. The use of human tissue was approved by the local ethics committee. Long-term ACE inhibitor treatment before surgery was evaluated in a retrospective manner. ACE inhibitor dosages prescribed by referring physicians were 31±5% of respective target dosages in recent heart failure megatrials. Twelve consecutive patients without ACE inhibitor pretreatment were matched with 12 patients with ACE inhibitor treatment according to New York Heart Association functional classification (2.2±0.2 for both groups). The groups showed no significant differences in systolic (116.3±5.1 mm Hg without ACE inhibition versus 113.1±5.1 mm Hg with ACE inhibition; P=0.66) or diastolic blood pressure (59.9±3.0 versus 62.2±2.7 mm Hg, respectively; P=0.57). In addition, no differences in central venous pressure, heart rate, left ventricular ejection fraction, age, sex, weight, or concomitant therapy with calcium antagonists, ß-blockers, diuretics, NO donors, antidiabetics, or lipid-lowering drugs were found.

Quantification of Human LOX-1 mRNA and Protein Expression
Total RNA from HUVECs and internal mammary artery biopsy samples was isolated by guanidinium thiocyanate/cesium chloride centrifugation. LOX-1 mRNA expression was quantified by standard calibrated competitive reverse transcriptase–polymerase chain reaction (RT-PCR) by use of a linker primer, PCR-generated, internal-deleted, and in vitro–transcribed LOX-1 standard cRNA. Western analysis of proteins from HUVECs (50 µg/lane) with or without Ang II stimulation with a LOX-1 monoclonal antibody was performed as described previously.⁹

Uptake of DiI-OxLDL in Human Endothelial Cells
LDL was isolated by sequential ultracentrifugation from human plasma, and oxidative modification of LDL with cupric ion was performed as previously described.¹¹ Oxidized LDL was labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI; Molecular Probes), and uptake of DiI-oxLDL for 3 hours was quantified as described.^{8 12}

Statistical Analysis
Data are shown as mean±SEM. Statistical analysis was performed with the ANOVA procedure followed by Dunnett's method (multiple comparison) or Student t test (SigmaStat software, Jandel Corp). Differences were taken as statistically significant at P<0.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Induction of LOX-1 Expression and OxLDL Uptake by Ang II in HUVECs
In HUVECs, Ang II maximally induces LOX-1 mRNA after 3 hours (Figure 1A; control: 6.9±1.4 relative units [RU]; 1 nmol/L Ang II: 8.0±2.6 RU; 10 nmol/L Ang II: 19.8±3.0 RU [P<0.05 versus control]; 100 nmol/L Ang II: 21.5±3.7 RU [P<0.05 versus control]; and 1 µmol/L Ang II: 23.1±5.5 RU [P<0.05 versus control]). This induction of LOX-1 mRNA was completely prevented by the AT₁ antagonist losartan (1 µmol/L) (control: 6.9±1.4 RU; 100 nmol/L Ang II: 21.5±3.7 RU [P<0.05 versus control]; 100 nmol/L Ang II plus 1 µmol/L losartan: 6.6±1.0 RU) (Figure 1B). In addition, incubation of HUVECs with Ang II (100 nmol/L, 3 hours) induced LOX-1 protein expression (212±21% of control level; n=6; P<0.01) (Figure 1C).

View larger version (20K): [in this window] [in a new window]   Figure 1. Ang II induces LOX-1 expression and oxLDL uptake in human endothelial cells. A, HUVECs were incubated with Ang II for 3 hours. LOX-1 mRNA expression was quantified by competitive RT-PCR. Ang II at concentrations >10 nmol/L induces LOX-1 mRNA. B, Induction of LOX-1 by Ang II is mediated by AT1. HUVECs were incubated with Ang II (100 nmol/L, 3 hours) in presence or absence of AT1 antagonist losartan (1 µmol/L). Losartan completely prevented induction of LOX-1 mRNA by Ang II. C, Ang II (100 nmol/L, 3 hours) induces LOX-1 protein expression in HUVECs. D, Functional activation of LOX-1 receptor by Ang II. Ang II (100 nmol/L) stimulates uptake of DiI-labeled oxLDL in human endothelial cells after 3 hours by an AT1-dependent pathway, reaching its maximum after 24 hours. Values for each bar are mean±SEM from 3 separate experiments. *P<0.05, **P<0.01 vs control (con) or indicated bar.

To verify this induction of LOX-1 at a functional level, HUVECs were incubated with Ang II (100 nmol/L), and uptake of DiI-labeled oxLDL was quantified (Figure 1D). Ang II stimulated uptake of oxLDL in human endothelial cells after 3 hours (209±17% of control level; P<0.05) by an AT₁-dependent pathway (100±3% with losartan), reaching its maximum after 24 hours (680±89%; P<0.05). The level of oxLDL uptake (2-fold induction after 3 hours) was similar to induction of LOX-1 mRNA and protein expression by Ang II.

Downregulation of LOX-1 mRNA by ACE Inhibitor Treatment
Because Ang II induces LOX-1 mRNA in vitro, we analyzed LOX-1 mRNA expression in internal mammary artery biopsy samples of patients with coronary heart disease with or without ACE inhibitor treatment (Figure 2). Long-term ACE inhibitor treatment causes significant downregulation of LOX-1 mRNA in internal mammary artery (without ACE inhibitor, 19.3±5.9 RU; ACE inhibitor, 6.4±2.0 RU; P<0.05; n=12 in each group). No significant correlation of LOX-1 mRNA expression with other medications could be found.

View larger version (17K): [in this window] [in a new window]   Figure 2. Downregulation of LOX-1 in internal mammary artery biopsy samples of patients with coronary heart disease by treatment with ACE inhibitors (ACE-I). RNA was isolated from biopsy samples of internal mammary artery prepared for CABG surgery. LOX-1 mRNA expression was quantified by competitive RT-PCR. Long-term ACE inhibitor treatment of patients causes significant downregulation of LOX-1 mRNA in internal mammary artery (*P<0.05, n=12 in each group).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Activation of oxLDL uptake is thought to play a key role in the initiation and progression of atherosclerosis.^{1 2} A major risk factor in the development of atherosclerosis and coronary heart disease is hypertension. It is associated with an activated tissue renin-angiotensin system. Our data show Ang II–mediated increased expression of the endothelial oxLDL receptor LOX-1 and augmented oxLDL uptake in human endothelial cells. These findings suggest a new mechanism to explain how hypertension might promote early initiation and progression of atherosclerosis. Increased Ang II levels would lead to stimulated uptake of proatherogenic oxLDL in endothelial cells. This could result in endothelial dysfunction by impaired endothelium-dependent arterial relaxation,³ infiltration of vessel wall with monocytes/macrophages by increased endothelial expression of adhesion molecules,⁴ and secretion of growth factors for vascular smooth muscle cells, resulting in vascular hypertrophy.⁵ Other early proatherosclerotic effects of oxLDL would include delay of endothelial wound healing, eg, by inhibition of migration of aortic endothelial cells into endothelial lesions; cytotoxicity to vascular cells, eg, through induction of oxidative stress; and induction of apoptosis in endothelial cells.^{2 6 7} Therefore, Ang II–stimulated oxLDL uptake into endothelial cells would accelerate early proatherosclerotic processes, before macrophage participation in the progression of atherosclerosis.

Recently, expression of LOX-1 also has been demonstrated in mature human monocyte–derived macrophages.¹³ Increased Ang II levels might therefore promote foam cell formation by LOX-1–mediated oxLDL uptake into both endothelial cells and macrophages.

The induction of LOX-1 by Ang II can be completely prevented by AT₁ receptor blockade. This finding suggests an antiatherosclerotic potential of pharmacological interventions in the renin-angiotensin system. This view is supported by the downregulation of LOX-1 expression by long-term ACE inhibition in internal mammary arteries of patients with coronary heart disease. This effect seems to be specific for the renin-angiotensin system, because neither group of patients showed a significant difference in blood pressure or concomitant therapy. Therefore, this effect might represent an antiatherosclerotic mechanism contributing to the vasoprotective potential of ACE inhibitors and the improved survival of patients in recent ACE inhibitor megatrials.

Conclusions
The endothelial receptor for oxLDL is upregulated by the renin-angiotensin system in vitro and in vivo. The downregulation of Ang II–stimulated LOX-1 expression might represent a novel mechanism contributing to the antiatherosclerotic potential of long-term ACE inhibitor treatment or AT₁ receptor blockade.

	Acknowledgments

 
We are grateful to E. Heinke, R. Gall, and R. Busath for excellent technical assistance. We deeply appreciate the cooperation and continuous support of patients and staff of the Clinic for Cardio-Thoracic Surgery, Martin Luther University, Halle-Wittenberg.

Received May 3, 1999; revision received July 7, 1999; accepted July 12, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Ross R. The pathogenesis of atherosclerosis: perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]

2. Steinberg D. Oxidative modification of LDL and atherogenesis. Circulation. 1997;94:1062–1071.

3. Kugiyama K, Kerns SA, Morrisett JD, Roberts R, Henry PD. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature. 1990;344:160–162.[Medline] [Order article via Infotrieve]

4. Khan BV, Parthasarathy SS, Alexander RW, Medford RM. Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J Clin Invest. 1995;95:1262–1270.

5. Chai YC, Howe PH, DiCorleto PE, Chisolm GM. Oxidized low density lipoprotein and lysophosphatidylcholine stimulate cell cycle entry in vascular smooth muscle cells: evidence for release of fibroblast growth factor-2. J Biol Chem. 1996;271:17791–17797.[Abstract/Free Full Text]

6. Galle J, Bengen J, Schollmeyer P, Wanner C. Impairment of endothelium-dependent dilation in rabbit renal arteries by oxidized lipoprotein(a): role of oxygen-derived radicals. Circulation. 1995;92:1582–1589.[Abstract/Free Full Text]

7. 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.[Abstract/Free Full Text]

8. 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.[Medline] [Order article via Infotrieve]

9. Kume N, Murase T, Moriwaki H, Aoyama T, Sawamura T, Masaki T, Kita T. Inducible expression of lectin-like oxidized LDL receptor-1 in vascular endothelial cells. Circ Res. 1998;83:322–327.[Abstract/Free Full Text]

10. Oka K, Sawamura T, Kikuta K, Itokawa S, Kume N, Kita T, Masaki T. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci U S A. 1998;95:9535–9540.[Abstract/Free Full Text]

11. Galle J, Wanner C. Oxidized LDL and Lp(a): preparation, modification, and analysis. In: Armstrong D, ed. Free Radical and Antioxidant Protocols. Totowa, NJ: Humana Press; 1998:119–130.

12. Stephan ZF, Yirachek EC. Rapid fluorometric assay of LDL receptor activity by DiI-labeled LDL. J Lipid Res. 1993;34:325–330.[Abstract]

13. Yoshida H, Kondratenko N, Green S, Steinberg D, Quehenberger O. Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor. Biochem J. 1998;334:9–13.

This article has been cited by other articles:

				M. Bohm, F. Mahfoud, C. Werner, K. Teo, and M. Baumhakel Cardiovascular protection: a breakthrough for high-risk patients Eur. Heart J. Suppl., December 1, 2009; 11(suppl_F): F19 - F26. [Abstract] [Full Text] [PDF]

				A. Goette, A. Bukowska, D. Dobrev, J. Pfeiffenberger, H. Morawietz, D. Strugala, I. Wiswedel, F.-W. Rohl, C. Wolke, S. Bergmann, et al. Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles Eur. Heart J., June 1, 2009; 30(11): 1411 - 1420. [Abstract] [Full Text] [PDF]

				D. Li and J. L. Mehta Intracellular Signaling of LOX-1 in Endothelial Cell Apoptosis Circ. Res., March 13, 2009; 104(5): 566 - 568. [Full Text] [PDF]

				C. Hu, A. Dandapat, L. Sun, M. R. Marwali, N. Inoue, F. Sugawara, K. Inoue, Y. Kawase, K.-i. Jishage, H. Suzuki, et al. Modulation of Angiotensin II-Mediated Hypertension and Cardiac Remodeling by Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Deletion Hypertension, September 1, 2008; 52(3): 556 - 562. [Abstract] [Full Text] [PDF]

				A. W. Krug, S. Kopprasch, C. G. Ziegler, S. Dippong, R. A. Catar, S. R. Bornstein, H. Morawietz, and M. Gekle Aldosterone Rapidly Induces Leukocyte Adhesion to Endothelial Cells: A New Link Between Aldosterone and Arteriosclerosis? Hypertension, November 1, 2007; 50(5): e156 - e157. [Full Text] [PDF]

				S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF]

				H. Morawietz LOX-1 and Atherosclerosis: Proof of Concept in LOX-1-Knockout Mice Circ. Res., June 8, 2007; 100(11): 1534 - 1536. [Full Text] [PDF]

				H. Morawietz, S. Erbs, J. Holtz, A. Schubert, M. Krekler, W. Goettsch, O. Kuss, V. Adams, K. Lenk, F. W. Mohr, et al. Endothelial Protection, AT1 Blockade and Cholesterol-Dependent Oxidative Stress: The EPAS Trial Circulation, July 4, 2006; 114(1_suppl): I-296 - I-301. [Abstract] [Full Text] [PDF]

				A. Ghazalpour, X. Wang, A. J. Lusis, and M. Mehrabian Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice Genetics, June 1, 2006; 173(2): 943 - 951. [Abstract] [Full Text] [PDF]

				O. Hofnagel, B. Luechtenborg, H. Eschert, G. Weissen-Plenz, N. J. Severs, and H. Robenek Pravastatin Inhibits Expression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) in Watanabe Heritable Hyperlipidemic Rabbits: A New Pleiotropic Effect of Statins Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 604 - 610. [Abstract] [Full Text] [PDF]

				J. L. Mehta, J. Chen, P. L. Hermonat, F. Romeo, and G. Novelli Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): A critical player in the development of atherosclerosis and related disorders Cardiovasc Res, January 1, 2006; 69(1): 36 - 45. [Abstract] [Full Text] [PDF]

				J.-i. Hinagata, M. Kakutani, T. Fujii, T. Naruko, N. Inoue, Y. Fujita, J. L. Mehta, M. Ueda, and T. Sawamura Oxidized LDL receptor LOX-1 is involved in neointimal hyperplasia after balloon arterial injury in a rat model Cardiovasc Res, January 1, 2006; 69(1): 263 - 271. [Abstract] [Full Text] [PDF]

				M.-S. Zhou, I. H. Schulman, P. J. Pagano, E. A. Jaimes, and L. Raij Reduced NAD(P)H Oxidase in Low Renin Hypertension: Link Among Angiotensin II, Atherogenesis, and Blood Pressure Hypertension, January 1, 2006; 47(1): 81 - 86. [Abstract] [Full Text] [PDF]

				Y. Takata, V. Chu, A. R. Collins, C. J. Lyon, W. Wang, F. Blaschke, D. Bruemmer, E. Caglayan, W. Daley, J. Higaki, et al. Transcriptional Repression of ATP-Binding Cassette Transporter A1 Gene in Macrophages: A Novel Atherosclerotic Effect of Angiotensin II Circ. Res., October 28, 2005; 97(9): e88 - e96. [Abstract] [Full Text] [PDF]

				K. Inoue, Y. Arai, H. Kurihara, T. Kita, and T. Sawamura Overexpression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Intramyocardial Vasculopathy in Apolipoprotein E-Null Mice Circ. Res., July 22, 2005; 97(2): 176 - 184. [Abstract] [Full Text] [PDF]

				H. L. Lazar Role of Angiotensin-Converting Enzyme Inhibitors in the Coronary Artery Bypass Patient Ann. Thorac. Surg., March 1, 2005; 79(3): 1081 - 1089. [Abstract] [Full Text] [PDF]

				T. Watanabe, T. A. Barker, and B. C. Berk Angiotensin II and the Endothelium: Diverse Signals and Effects Hypertension, February 1, 2005; 45(2): 163 - 169. [Abstract] [Full Text] [PDF]

				D. H. Endemann and E. L. Schiffrin Endothelial Dysfunction J. Am. Soc. Nephrol., August 1, 2004; 15(8): 1983 - 1992. [Abstract] [Full Text] [PDF]

				I. V. Smirnova, M. Kajstura, T. Sawamura, and M. S. Goligorsky Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H782 - H790. [Abstract] [Full Text] [PDF]

				K. Grote, H. Drexler, and B. Schieffer Renin-angiotensin system and atherosclerosis Nephrol. Dial. Transplant., April 1, 2004; 19(4): 770 - 773. [Full Text] [PDF]

				W.J. Remme Reconsider the management of all coronary artery disease patients: Importance of the EUROPA trial Eur. Heart J. Suppl., July 1, 2003; 5(suppl_E): E23 - E30. [Abstract] [PDF]

				D. S. Jacoby and D. J. Rader Renin-Angiotensin System and Atherothrombotic Disease: From Genes to Treatment Arch Intern Med, May 26, 2003; 163(10): 1155 - 1164. [Abstract] [Full Text] [PDF]

				U. Landmesser and H. Drexler Oxidative stress, the renin-angiotensin system, and atherosclerosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A3 - A7. [Abstract] [PDF]

				N. Werner and G. Nickenig AT1 receptors in atherosclerosis: biological effects including growth, angiogenesis, and apoptosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A9 - A13. [Abstract] [PDF]

				D. Li, R. M. Singh, L. Liu, H. Chen, B. M. Singh, N. Kazzaz, and J. L. Mehta Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells Cardiovasc Res, January 1, 2003; 57(1): 238 - 243. [Abstract] [Full Text] [PDF]

				U. Rueckschloss, M. T. Quinn, J. Holtz, and H. Morawietz 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, November 1, 2002; 22(11): 1845 - 1851. [Abstract] [Full Text] [PDF]

				A. R. Brasier, A. Recinos III, and M. S. Eledrisi Vascular Inflammation and the Renin-Angiotensin System Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1257 - 1266. [Abstract] [Full Text] [PDF]

				J. R Chiong and A. B Miller Review: Renin-angiotensin system antagonism and lipid-lowering therapy in cardiovascular risk management Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 96 - 102. [Abstract] [PDF]

				J. L. Mehta and D. Li Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1429 - 1435. [Abstract] [Full Text] [PDF]

				G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part I: Oxidative Stress and Atherogenesis Circulation, January 22, 2002; 105(3): 393 - 396. [Full Text] [PDF]

				U. Rueckschloss, J. Galle, J. Holtz, H.-R. Zerkowski, and H. Morawietz 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, October 9, 2001; 104(15): 1767 - 1772. [Abstract] [Full Text] [PDF]

				A. Rozanski, E. Qureshi, M. Bauman, G. Reed, G. Pillar, and G. A. Diamond Peripheral Arterial Responses to Treadmill Exercise Among Healthy Subjects and Atherosclerotic Patients Circulation, April 24, 2001; 103(16): 2084 - 2089. [Abstract] [Full Text] [PDF]

				X Shi, S Niimi, T Ohtani, and S Machida Characterization of residues and sequences of the carbohydrate recognition domain required for cell surface localization and ligand binding of human lectin-like oxidized LDL receptor J. Cell Sci., January 4, 2001; 114(7): 1273 - 1282. [Abstract] [PDF]

				A. Schubert, M. Cattaruzza, M. Hecker, D. Darmer, J. Holtz, and H. Morawietz Shear Stress-Dependent Regulation of the Human {beta}-Tubulin Folding Cofactor D Gene Circ. Res., December 8, 2000; 87(12): 1188 - 1194. [Abstract] [Full Text] [PDF]

				J. O. Toikka, H. Laine, M. Ahotupa, A. Haapanen, J. S. A. Viikari, J. J. Hartiala, and O. T Raitakari Increased Arterial Intima-Media Thickness and In Vivo LDL Oxidation in Young Men With Borderline Hypertension Hypertension, December 1, 2000; 36(6): 929 - 933. [Abstract] [Full Text] [PDF]

				H. Morawietz, R. Talanow, M. Szibor, U. Rueckschloss, A. Schubert, B. Bartling, D. Darmer, and J. Holtz Regulation of the endothelin system by shear stress in human endothelial cells J. Physiol., June 15, 2000; 525(3): 761 - 770. [Abstract] [Full Text] [PDF]

				M. Kakutani, T. Masaki, and T. Sawamura A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 PNAS, January 4, 2000; 97(1): 360 - 364. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morawietz, H. Articles by Holtz, J. Search for Related Content PubMed PubMed Citation Articles by Morawietz, H. Articles by Holtz, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Coronary Artery Disease Hazardous Substances DB LOSARTAN POTASSIUM Related Collections Lipids ACE/Angiotension receptors Pathophysiology Chronic ischemic heart disease Mechanism of atherosclerosis/growth factors