Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 expression: is it right now a safe and promising therapeutic approach for atherosclerosis?

Lectin -like oxidized(ox) LDL receptor-1 (LOX-1) is the major receptor for oxLDL; several studies in vitro and in animal models have shown that LOX-1 is involved in almost all proatherogenic effects of oxLDL. Growing evidence also demonstrated that LOX-1 plays a role not only in the initiation and formation, but also in plaque destabilization and rupture and strengthen the role of this receptor in cardiovascular disease. As several studies gathered from animal models, as well as genetic studies, support the hypothesis that the binding and internalization of oxLDL by scavenger receptors such as LOX-1 triggers a series of mechanisms leading to endothelial dysfunction and foam cell formation, modulation of LOX-1 levels has been suggested to be one therapeutic route in attenuating early events in atherosclerosis. This is an editorial comment to a paper in which the authors designed a pyrrole–imidazole polyamide to bind to a proximal site of the AP-1 binding region in the LOX-1 gene promoter. This molecule interfered with AP-1 protein binding to the LOX-1 gene promoter and inhibited the phorbol myristate acetate-mediated enhancement of LOX-1 gene expression in human umbilical vein endothelial cells and decreased apoptosis induced by Angiotensin II and oxLDL in HUVECs. As pyrrole–imidazole polyamide was efficacious in inhibition of LOX-1 expression and apoptosis, which has been shown to be associated with the vulnerability of plaques, the authors propose the use of this agent for the study and treatment of atherosclerotic disease. Although silencing LOX-1 expression opens an appealing scenario on treatment of atherosclerosis, some important questions remain to be elucidated before translating fascinating results, obtained in vitro and in animal models, to patients. Further studies on inhibition of LOX-1 expression or drugs targeting LOX-1 may help to enlighten these open issue