Abstract 77: Endothelial LOX-1 Protects Against Arterial Thrombosis via Activation of the Oct-1/SIRT1 Pathway

Abstract

Background: The lectin-like oxLDL receptor-1 (LOX-1) promotes the endothelial uptake of oxidized low-density lipoprotein (oxLDL). However, LOX-1 is involved in several other biological processes and its role in arterial thrombus formation remains unknown. The present study was designed to investigate whether LOX-1 activation plays a role in thrombus formation in vivo. Methods and Results: Endothelial-specific LOX-1 transgenic mice were generated using the Tie2 promoter (LOX-1TG). While plasma levels of oxLDL were comparable, carotid tissue oxLDL content was markedly increased in LOX-1TG as compared to wild type (WT). Arterial thrombus formation was assessed using an in vivo photochemical injury model. Time to arterial occlusion was prolonged in LOX-1TG as compared to WT. In line with this, tissue factor (TF) expression and activity were reduced by 50% in the carotid arteries of LOX-1TG mice. This effect was mediated by the activation of the transcription factor Oct-1 leading to upregulation of mammalian deacetylase SIRT1 via binding to its promoter and subsequent inhibition of NF-κB signaling as demonstrated by siRNA experiments. This was further confirmed in LOX-1TG endothelial cells (EC) where expression of Oct-1 and SIRT1 was increased upon exposure to oxLDL. Increased expression of SIRT1 was further associated with decreased DNA-binding of RelA/p65 subunit of NF-κB. Conclusions: LOX-1 activates a novel compensatory pathway which protects against arterial thrombus formation in vivo. These unexpected findings suggest that Oct-1/SIRT1 signaling may represent a novel target for the prevention of arterial thrombus formation in the setting of hyperlipidemia and atherosclerosis.