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

Abstract

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 microM) or N(G)-nitro-l-arginine methyl ester (l-NAME, 300 microM), 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.

Asymmetrical Dimethylarginine Predicts Progression to Dialysis and Death in Patients with Chronic Kidney Disease

“…In renal failure, ADMA accumulation only in part depends on compromised excretory function in that it was shown that reduced dimethylarginine dimethylaminohydrolase activity may contribute substantially to ADMA accumulation (29). The wide-range involvement of ADMA in the atherosclerosis process is epitomized by recent in vitro findings indicating that ADMA contributes to macrophage lipid accumulation, which is a critical step in the formation of fatty streaks during atherogenesis (30). In this cohort, the vast majority of deaths (61%) were cardiovascular in nature.…”

Prominent Lectin-Like Oxidized Low Density Lipoprotein (LDL) Receptor-1 (LOX-1) Expression in Atherosclerotic Lesions Is Associated with Tissue Factor Expression and Apoptosis in Hypercholesterolemic Rabbits

“…6) Recent studies with cultured cells suggest that LOX-1 may play several important roles in destabilization of atherosclerotic plaques, inducing expression of adhesion molecules and chemokines for monocytes, 7) transformation of macrophages into foam cells, 8,9) apoptosis of smooth muscle cells 10,11) and the degradation of extracellular matrix proteins by induction of matrix metalloproteinases.…”

“…3) Lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1), a type II membrane glycoprotein belonging to the C-type lectin family, acts as a cell-surface receptor for oxidized LDL (Ox-LDL) and mediates several biological effects of Ox-LDL. 6) Recent studies with cultured cells suggest that LOX-1 may play several important roles in destabilization of atherosclerotic plaques, inducing expression of adhesion molecules and chemokines for monocytes, 7) transformation of macrophages into foam cells, 8,9) apoptosis of smooth muscle cells 10,11) and the degradation of extracellular matrix proteins by induction of matrix metalloproteinases.…”

Serum sLOX-1 levels are associated with the presence and severity of angiographic coronary artery disease in patients with metabolic syndrome

“…e involvement of LOX-1 in the development of atherosclerosis resulting from MetS has been suggested by the fact that the cardiovascular risk factors of MetS are closely associated with the upregulation of LOX-1. Dyslipidemia, particularly increased plasma level of ox-LDL, plays the major role in the upregulation of LOX- [27], and production of matrix metalloproteinases [28], resulting in cell injury that facilitates atherosclerotic plaque formation and progression. Our results suggest that LOX-1 plays a pivotal role in the cross-talk between MetS and CAD, and high sLOX-1 level could perhaps be used to predict the occurrence of future cardiovascular events in patients with MetS.…”

“…Recent studies have also found that circulating levels of sLOX-1 are signi cantly increased in metabolic disorders, including obesity [11] and type 2 DM [12], and are positively correlated with reduction in body weight [13]. e activation of LOX-1 is involved in endothelial ECs dysfunction [25], apoptosis of VSMCs [26], accumulation of lipids in macrophages [27], and production of matrix metalloproteinases [28], resulting in cell injury that facilitates atherosclerotic plaque formation and progression. Our results suggest that LOX-1 plays a pivotal role in the cross-talk between MetS and CAD, and high sLOX-1 level could perhaps be used to predict the occurrence of future cardiovascular events in patients with MetS.…”