HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/2/H782    most recent 00822.2003v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (31) Citing Articles via Google Scholar Google Scholar Articles by Smirnova, I. V. Articles by Goligorsky, M. S. Search for Related Content PubMed PubMed Citation Articles by Smirnova, I. V. Articles by Goligorsky, M. S.

Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation

Departments of ¹Medicine and ²Pathology, Renal Research Institute and Division of Nephrology, New York Medical College, Valhalla, New York 10595; and ³Department of Bioscience, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

Submitted 26 August 2003 ; accepted in final form 8 March 2004

Intimal infiltration by monocytes and accumulation of lipids represent a critical step in the formation of fatty streaks during atherogenesis. Because elevated plasma levels of asymmetric dimethylarginine (ADMA), a potent nitric oxide (NO) synthase (NOS) inhibitor, are prevalent in diverse cardiovascular diseases, the goal of this study was to examine the contribution of NO deficiency to macrophage lipid accumulation. Inhibition of NO synthesis in PMA-primed human monocytic leukemia HL-60 cells resulted in a twofold increase in expression of the receptor for oxidized LDL (OxLDL), termed the lectin-like OxLDL receptor (LOX-1). Blockade of inducible NOS in activated macrophages resulted in 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-OxLDL accumulation and imparted macrophages with a foamy appearance as detected with oil-red O lipid staining. ADMA (15 µM) or N^G-nitro-L-arginine methyl ester (L-NAME, 300 µM), both of which suppress inducible NOS activity, increased oil-red staining 1.9- and 2.8-fold, respectively. Macrophages treated with ADMA or L-NAME showed a 2.4-fold increase in accumulation of DiI-OxLDL. To examine the role of LOX-1 in this process, we used small interfering RNA (siRNA) duplex-mediated LOX-1 gene silencing. LOX-1 expression was suppressed twofold by siRNA as shown by Western blot analysis. This suppression was associated with a two- to fourfold decrease in DiI-OxLDL uptake as identified by fluorescence microscopy and decreased oil-red O staining by activated macrophages. In conclusion, accumulation of ADMA (a competitive inhibitor of NOS) in patients with chronic renal failure may be responsible for upregulation of LOX-1 receptor and increased OxLDL uptake, thus contributing to lipidosis and foam cell formation. The data illustrate an additional nonendothelial mode of antiatherogenic action of NO: prevention of LOX-1 induction and lipid accumulation by macrophages.

lectin-like oxidized low-density lipoprotein receptor-1; nitric oxide; renal failure; atherogenesis

This article has been cited by other articles:

				D. F. Schaeffer, M. Riazy, K. S. Parhar, J. H. Chen, V. Duronio, T. Sawamura, and U. P. Steinbrecher LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma J. Lipid Res., August 1, 2009; 50(8): 1676 - 1684. [Abstract] [Full Text] [PDF]

				Q. G. Zhou, M. Zhou, F. F. Hou, and X. Peng Asymmetrical dimethylarginine triggers lipolysis and inflammatory response via induction of endoplasmic reticulum stress in cultured adipocytes Am J Physiol Endocrinol Metab, April 1, 2009; 296(4): E869 - E878. [Abstract] [Full Text] [PDF]

				A. Stoessel, A. Paliege, F. Theilig, F. Addabbo, B. Ratliff, J. Waschke, D. Patschan, M. S. Goligorsky, and S. Bachmann Indolent course of tubulointerstitial disease in a mouse model of subpressor, low-dose nitric oxide synthase inhibition Am J Physiol Renal Physiol, September 1, 2008; 295(3): F717 - F725. [Abstract] [Full Text] [PDF]

				J. E. Murphy, R. S. Vohra, S. Dunn, Z. G. Holloway, A. P. Monaco, S. Homer-Vanniasinkam, J. H. Walker, and S. Ponnambalam Oxidised LDL internalisation by the LOX-1 scavenger receptor is dependent on a novel cytoplasmic motif and is regulated by dynamin-2 J. Cell Sci., July 1, 2008; 121(13): 2136 - 2147. [Abstract] [Full Text] [PDF]

				E. Monsalve, P. J. Oviedo, M. A. Garcia-Perez, J. J. Tarin, A. Cano, and C. Hermenegildo Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells Cardiovasc Res, January 1, 2007; 73(1): 66 - 72. [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]

				P. Ravani, G. Tripepi, F. Malberti, S. Testa, F. Mallamaci, and C. Zoccali Asymmetrical Dimethylarginine Predicts Progression to Dialysis and Death in Patients with Chronic Kidney Disease: A Competing Risks Modeling Approach J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2449 - 2455. [Abstract] [Full Text] [PDF]

				J. E. Barbato, B. S. Zuckerbraun, M. Overhaus, K. G. Raman, and E. Tzeng Nitric oxide modulates vascular inflammation and intimal hyperplasia in insulin resistance and the metabolic syndrome Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H228 - H236. [Abstract] [Full Text] [PDF]

				M. S. Goligorsky Endothelial cell dysfunction: can't live with it, how to live without it Am J Physiol Renal Physiol, May 1, 2005; 288(5): F871 - F880. [Abstract] [Full Text] [PDF]