Low Density Lipoproteins Downregulate Lysyl Oxidase in Vascular Endothelial Cells and the Arterial Wall

Abstract

Objective-Hypercholesterolemia induces endothelial dysfunction, a hallmark of the atherosclerotic process, modulating the expression of key genes in vascular endothelial cells. Methods and Results-By differential display analysis, we have studied the effect of high concentrations of native low density lipoprotein (LDL) on endothelial gene expression. mRNA levels of lysyl oxidase (LOX), an enzyme involved in collagen and elastin cross-linking, were downregulated by LDL treatment in endothelial cells in a dose-and time-dependent manner (80% of inhibition by 180 mg/dL LDL for 24 hours). This reduction of LOX expression was associated with a decrease in LOX activity (40% and 54% of inhibition after 24 and 48 hours of LDL treatment, respectively). LOX mRNA half-life was not modified by LDL, but transcriptional inhibition blocked the effect of LDL. Inhibition of LOX activity by either LDL or ␤-aminopropionitrile, an inhibitor of LOX, increased endothelial permeability (192Ϯ0.19-and 3.37Ϯ0.74-fold, respectively). Interestingly, a reduction in LOX expression (3.5-fold) was observed in vivo in the vascular wall of hypercholesterolemic pigs. Conclusions-These findings suggest that LDL downregulation of LOX could contribute to the endothelial dysfunction caused by hypercholesterolemia, thus contributing to atherosclerotic plaque formation. (Arterioscler Thromb Vasc Biol. 2002;22:1409-1414.)Key Words: endothelial cells Ⅲ low density lipoproteins Ⅲ lysyl oxidase Ⅲ vascular permeability Ⅲ hypercholesterolemia V ascular endothelium acts as a selective barrier, controlling the exchange of macromolecules between blood and the underlying tissues and regulating vascular tone and the thrombogenic/fibrinolytic balance. Endothelial dysfunction associated with hypercholesterolemia is one of the earlier events in the atherosclerotic process. The alteration of endothelial gene expression by high concentrations of LDL leads to a decrease in NO bioavailability [1][2][3] and to an increase in leukocyte recruitment by an induction of adhesion molecule expression. 4 See page 1365It has been reported that atherogenic concentrations of LDL alter the composition and permeability of the endothelial barrier by inducing changes in the basement membrane. 5 Thus, the alteration in endothelial extracellular matrix (ECM) could play a key role in the endothelial dysfunction associated with hypercholesterolemia. One of the key enzymes involved in ECM maturation is lysyl oxidase (LOX). This enzyme, a copper-containing semicarbazide-sensitive amine oxidase, 6 initiates the covalent cross-linking of collagen and elastin that is essential in maintaining ECM structure. LOX oxidatively deaminates peptidyl lysine residues of collagen and elastin, leading to the synthesis of peptidyl aldehydes, which condense spontaneously to form the mature and insoluble ECM. 7 LOX has also been associated with tumor supression 8,9 and chemotaxis, 10 and in the last few years, different LOX isoforms, probably with different substrate specificity and function, have been identif...

Lysyl oxidase (LOX) limits VSMC proliferation and neointimal thickening through its extracellular enzymatic activity

“…We have previously shown the critical contribution of LOX to the control of endothelial homeostasis 16–19 and to the regulation of vascular remodeling by modulating cell proliferation, ECM calcification and ROS production 15,20,28 . Neointimal thickening induced by carotid artery injury was attenuated in a transgenic mouse model that specifically over-expresses LOX in VSMC, consistent with the lower proliferative rates exhibited by VSMC from these animals 20 .…”

Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell

“…One might question whether the chemotactic activity of LO contributes to the chronic nature of this disease by maintaining the migration of medial VSMC to the sites of the intimal lesions and/or the migration of inflammatory blood monocytes through the vascular endothelium. The potential participation of LO in arterial disease is also inferred by the recent report that low density lipoproteins downregulate the expression of LO in vascular endothelial cells [Rodriguez et al, 2002].…”

Nanoarchitecture of scaffolds and endothelial cells in engineering small diameter vascular grafts

“…Thrombospondins, a family of secreted glycoproteins, are localized in the endothelial basement membrane and are found to regulate angiogenesis by interacting with TGF‐β1 and MMP 2 [53]. The significant roles of ECM nanofibers in the expression of various genes specific to ECs are described in Table 1 [54–64].…”

“…Hence, a combination of trophic factors in the ECM analog (nanofibers) could be an integrative approach to trigger the inter‐ and intra‐cellular signaling cascades (Fig. 3) [64, 90–95].…”