(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).
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
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
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