Small-sized low-density lipoproteins of subclass B from patients with end-stage renal disease effectively augment tumor necrosis factor-α-induced adhesive properties in human endothelial cells

Increased prevalence of small-sized low-density lipoprotein (LDL) subclass B (diameter < 25.5 nm) possibly Is involved in the multifactorial process of cardiovascular disease in patients with end-stage renal disease. Given these epidemiological observations, mechanisms underlying the combined effect of a proinflammatory Insult and LDL of different subclasses (subclass A, diameter > 25.5 nm, and subclass B) in a cellular model were investigated. For this, human umbilical vein endothelial cells were preexposed to LDL, then stimulated with tumor necrosis factor-alpha (TNF-alpha). Modulatory effects of LDL phenotypes on the activation of adhesion molecules, monocyte :adherence, and transcriptional activity of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) were Investigated. Our data show that subclass B LDLs were metabolized through nonspecific scavenger receptors and specific LDL-receptor pathways in endothelial cells. Furthermore, LDL subclass B in comparison to subclass A more effectively enhanced monocyte recruitment and adhesive properties of endothelial cells in response to TNF-alpha. These effects appeared not to be mediated by oxidative stress-responsive NF-kappaB because modulation of this transcription factor by LDL was moderate and similar for both LDL phenotypes. Conversely, effects of LDL subclass B were considered to be caused by augmented AP-1 binding activity. In conclusion, the present model provides new clues in atherogenic mechanisms of small-sized LDLs, which sensitize vascular cells to inflammatory signals more effectively than normal-sized LDLs. (C) 2002 by the National Kidney Foundation, Inc.