Lysyl oxidase (LOX) plays a crucial role in the maintenance of extracellular matrix stability and could participate in vascular remodelling associated with cardiovascular diseases. Evidence from in vitro and in vivo studies shows that LOX downregulation is associated with the endothelial dysfunction characteristic of earlier stages of the atherosclerotic process. Conversely, upregulation of this enzyme in vascular cells could induce neointimal thickening in atherosclerosis and restenosis. In fact, LOX is chemotactic for vascular smooth muscle cells and monocytes, is modulated by proliferative stimulus in these cells, and could control other cellular processes such as gene expression and cell transformation. Furthermore, it is conceivable that LOX downregulation could underlie plaque instability and contribute to the destructive remodelling that takes place during aneurysm development. Overall, LOX could play a key role in vascular homeostasis and, hence, it emerges as a new player in cardiovascular diseases. This review addresses the experimental evidence related to the role of LOX in vascular disorders and the potential benefits of controlling its expression and function.

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Abstract-Atherogenic levels of native low density lipoproteins (nLDLs) decrease the bioavailability of endotheliumderived NO and downregulate endothelial NO synthase (eNOS) expression in cultured human endothelial cells. Here, we show that simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, within the therapeutic range (0.01 to 1 mol/L) prevented the downregulation of eNOS mRNA and protein promoted by nLDL (180 mg cholesterol/dL, 48 hours) in human umbilical vein endothelial cells. This effect of simvastatin was completely reversed by mevalonate, the product of the reaction, and to a lesser extent by farnesol and geranyl geraniol. Simvastatin significantly stabilized eNOS mRNA in cells treated with nLDL during 48 hours (eNOS mRNA half-life Ϸ11 hours in controls versus Ͼ24 hours in nLDL per 0.1 mol/L simvastatin-treated cells). The downregulation of eNOS by nLDL was abrogated by cycloheximide, an inhibitor of protein synthesis, and by N-acetyl-leucyl-leucyl-norleucinal, a protease inhibitor that reduces the catabolism of sterol regulatory element binding proteins. Sterol deprivation increased the downregulation produced by nLDL on eNOS and sterol regulatory element binding protein-2 expression levels. However, no differential modulation of the retardation bands corresponding to the putative sterol-responsive element present in the eNOS promoter was detected by electrophoretic mobility shift assay. Our results suggest that nLDL promote eNOS downregulation operating at a transcriptional level, whereas simvastatin prevents such an effect through a posttranscriptional mechanism. H ypercholesterolemia produces endothelial dysfunction and early impairment of endothelium-dependent vasodilatation associated with a reduced bioavailability of NO. 1 Conversely, one of the earliest benefits of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), drugs that reduce cardiac morbility and mortality, 2,3 is the improvement of endothelium-dependent relaxation. 4 Because NO is involved in virtually all endotheliumdependent protective effects, 5 statins could indirectly modulate all these events through a regulation of NO production.Cholesterol lowering could contribute to the improvement of endothelium-dependent vasodilatation. It has been suggested that treatment of elevated plasma cholesterol levels reduces the oxidative stress within the vessel wall, subsequently preventing inactivation of NO by free radicals. 6 In addition, the NO-dependent improvement in forearm blood flow observed in fluvastatin-treated patients was weakly but significant related to a reduction in the level of plasma LDL cholesterol. 7 However, the restoration of endothelial function sometimes occurs before significant reduction in serum cholesterol levels. 4,8 In addition, Williams et al 9 have shown that the response to acetylcholine of coronary arteries from pravastatin-treated monkeys was better than that of untreated animals with similar plasma cholesterol levels. Recent evidences suggest a direct effect o...

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