Alexander Akhmedov1,2,3, Giovanni G Camici1,2,3, Martin F Reiner1,2,3,4, Nicole R Bonetti1,2,3, Sarah Costantino1,2,3,5, Erik W Holy1,2,3, Remo D Spescha1,2,3, Simona Stivala1,2,3,4, Ariane Schaub Clerigué1,2,3, Thimoteus Speer1,2,3,6, Alexander Breitenstein1,2,3, Jasmin Manz1,2,3, Christine Lohmann1,2,3, Francesco Paneni1,2,3,5, Juerg-Hans Beer4, Thomas F Lüscher1,2,3. 1. Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland. 2. Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland. 3. Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland. 4. Division of Internal Medicine, Cantonal Hospital Baden, Im Ergel 1, CH-5404 Baden, Switzerland. 5. Cardiology Unit, Department of Medicine, Karolinska University Hospital, Karolinska vägen, 171 76 Solna, Stockholm, Sweden. 6. Department of Internal Medicine 4, Saarland University Hospital, Kirrberger Str. 100, D-66424 Homburg, Saarland, Germany.
Abstract
AIMS: The lectin-like oxLDL receptor-1 (LOX-1) promotes endothelial uptake of oxidized low-density lipoprotein (oxLDL) and plays an important role in atherosclerosis and acute coronary syndromes (ACS). However, its role in arterial thrombus formation remains unknown. We investigated whether LOX-1 plays a role in arterial thrombus formation in vivo at different levels of oxLDL using endothelial-specific LOX-1 transgenic mice (LOX-1TG) and a photochemical injury thrombosis model of the carotid artery. METHODS AND RESULTS: In mice fed a normal chow diet, time to arterial occlusion was unexpectedly prolonged in LOX-1TG as compared to WT. In line with this, tissue factor (TF) expression and activity in carotid arteries of LOX-1TG mice were reduced by half. This effect was mediated by activation of octamer transcription factor 1 (Oct-1) leading to upregulation of the mammalian deacetylase silent information regulator-two 1 (SIRT1) via binding to its promoter and subsequent inhibition of NF-κB signaling. In contrast, intravenous injection of oxLDL as well as high cholesterol diet for 6 weeks led to a switch from the Oct-1/SIRT1 signal transduction pathway to the ERK1/2 pathway and in turn to an enhanced thrombotic response with shortened occlusion time. CONCLUSIONS: Thus, LOX-1 differentially regulates thrombus formation in vivo depending on the degree of activation by oxLDL. At low oxLDL levels LOX-1 activates the protective Oct-1/SIRT1 pathway, while at higher levels of the lipoprotein switches to the thrombogenic ERK1/2 pathway. These findings may be important for arterial thrombus formation in ACS and suggest that SIRT1 may represent a novel therapeutic target in this context. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The lectin-like oxLDL receptor-1 (LOX-1) promotes endothelial uptake of oxidized low-density lipoprotein (oxLDL) and plays an important role in atherosclerosis and acute coronary syndromes (ACS). However, its role in arterial thrombus formation remains unknown. We investigated whether LOX-1 plays a role in arterial thrombus formation in vivo at different levels of oxLDL using endothelial-specific LOX-1 transgenic mice (LOX-1TG) and a photochemical injury thrombosis model of the carotid artery. METHODS AND RESULTS: In mice fed a normal chow diet, time to arterial occlusion was unexpectedly prolonged in LOX-1TG as compared to WT. In line with this, tissue factor (TF) expression and activity in carotid arteries of LOX-1TG mice were reduced by half. This effect was mediated by activation of octamer transcription factor 1 (Oct-1) leading to upregulation of the mammalian deacetylase silent information regulator-two 1 (SIRT1) via binding to its promoter and subsequent inhibition of NF-κB signaling. In contrast, intravenous injection of oxLDL as well as high cholesterol diet for 6 weeks led to a switch from the Oct-1/SIRT1 signal transduction pathway to the ERK1/2 pathway and in turn to an enhanced thrombotic response with shortened occlusion time. CONCLUSIONS: Thus, LOX-1 differentially regulates thrombus formation in vivo depending on the degree of activation by oxLDL. At low oxLDL levels LOX-1 activates the protective Oct-1/SIRT1 pathway, while at higher levels of the lipoprotein switches to the thrombogenic ERK1/2 pathway. These findings may be important for arterial thrombus formation in ACS and suggest that SIRT1 may represent a novel therapeutic target in this context. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Alexander Akhmedov; Nicole R Bonetti; Martin F Reiner; Remo D Spescha; Heidi Amstalden; Mario Merlini; Daniel S Gaul; Candela Diaz-Cañestro; Sylvie Briand-Schumacher; Rebecca S Spescha; Aurora Semerano; Giacomo Giacalone; Gianluigi Savarese; Fabrizio Montecucco; Luka Kulic; Roger M Nitsch; Christian M Matter; Gerd A Kullak-Ublick; Maria Sessa; Thomas F Lüscher; Jürg H Beer; Luca Liberale; Giovanni G Camici Journal: J Cereb Blood Flow Metab Date: 2018-08-03 Impact factor: 6.200