Lysyl oxidase and endothelial dysfunction: mechanisms of lysyl oxidase down-regulation by pro-inflammatory cytokines.
Lysyl oxidase (LOX) plays a pivotal role in extracellular matrix (ECM) maturation. Furthermore, novel biological functions has been ascribed to LOX, among them cell differentiation, migration, transformation and regulation of gene expression. In this context, it has been suggested that abnormalities of LOX expression could underlie the development of multiple pathological processes including cardiovascular diseases. LOX seems to be crucial in the preservation of endothelial barrier function. In fact, accumulating evidences suggest a role of this enzyme in atherogenesis and endothelial dysfunction triggered by atherosclerotic risk factors and pro-inflammatory cytokines. Indeed, cytokines such as tumour necrosis factor-alpha (TNF-alpha) modulate vascular LOX expression. This cytokine decreases LOX expression and activity in endothelial cells through a transcriptional mechanism that involves TNF receptor-2 and protein kinase C activation. Interestingly, in vivo studies reveal that TNF-alpha causes a down-regulation of vascular LOX expression. Thus, LOX down-regulation seems to be associated to the endothelial dysfunction elicited by multiple pathological factors. LOX rises as a promising target gene for the development of therapeutic strategies in the treatment of cardiovascular diseases.
Alcudia
Javier F
JF
Centro de Investigacion Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, c/Antoni Ma Claret 167, 08025 Barcelona, Spain.
Martinez-Gonzalez
Jose
J
Guadall
Anna
A
Gonzalez-Diez
Maria
M
Badimon
Lina
L
Rodriguez
Cristina
C
D000818:Animals; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000201:enzymology; D007249:Inflammation; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D008249:Protein-Lysine 6-Oxidase; D011493:Protein Kinase C