Endothelial SIRT6 deficiency promotes arterial thrombosis in mice. (January 2023)

• Record Type: Journal Article
• Authors: Gaul, Daniel S.; Calatayud, Natacha; Pahla, Jürgen; Bonetti, Nicole R.; Wang, Yu-Jen; Weber, Julien; Ambrosini, Samuele; Liberale, Luca; Costantino, Sarah; Mohammed, Shafeeq A.; Kraler, Simon; Van Tits, Lambertus J.; Pasterk, Lisa; Vdovenko, Daria; Akhmedov, Alexander; Ruschitzka, Frank; Paneni, Francesco; Lüscher, Thomas F.; Camici, Giovanni G.; Matter, Christian M.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 174(2023)
• Page Start: 56
• Page End: 62
• Publication Date: 2023-01
• Subjects: SIRT6 -- Endothelium -- Tissue factor -- Arterial thrombosis; AP-1 activator protein 1 -- COX cyclooxygenase -- eNOS endothelial nitric oxide synthase -- GAPDH glycerinealdehyde 3-phosphate dehydrogenase -- GFP green fluorescent protein -- HAECs human aortic endothelial cells -- ICAM-1 intracellular adhesion molecule 1 -- MAPK mitogen-activated protein kinase -- MCP-1 monocyte chemoattractant protein 1 -- NAD+ nicotinamide adenine dinucleotide -- NF-κB nuclear factor kappa B -- NFκBIα NF-κB inhibitor alpha -- PARP-1 poly [ADP-ribose] polymerase 1 -- SCR scrambled -- SIRT6 sirtuin 6 -- TF tissue factor -- TNF-α tumor necrosis factor alpha -- VCAM-1 vascular cell adhesion molecule 1; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2022.11.005
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Objective: Arterial thrombosis may be initiated by endothelial inflammation or denudation, activation of blood-borne elements or the coagulation system. Tissue factor (TF), a central trigger of the coagulation cascade, is regulated by the pro-inflammatory NF-κB-dependent pathways. Sirtuin 6 (SIRT6) is a nuclear member of the sirtuin family of NAD + -dependent deacetylases and is known to inhibit NF-κB signaling. Its constitutive deletion in mice shows early lethality with hypoglycemia and accelerated aging. Of note, the role of SIRT6 in arterial thrombosis remains unknown. Thus, we hypothesized that endothelial SIRT6 protects from arterial thrombosis by modulating inhibition of NF-κB-associated pathways. Approach and results: Using a laser-induced carotid thrombosis model, in vivo arterial occlusion occurred 45% faster in 12-week-old male endothelial-specific Sirt6 −/− mice as compared to Sirt6 fl/fl controls ( n ≥ 9 per group; p = 0.0012). Levels of procoagulant TF were increased in animals lacking endothelial SIRT6 as compared to control littermates. Similarly, in cultured human aortic endothelial cells, SIRT6 knockdown increased TF mRNA, protein and activity. Moreover, SIRT6 knockdown increased mRNA levels of NF-κB-associated genes tumor necrosis factor alpha ( TNF- α), poly [ADP-ribose] polymerase 1 ( PARP-1 ), vascular cell adhesion molecule 1 ( VCAM-1 ), and cyclooxygenase-2 ( COX-2 ); at the protein level, COX-2, VCAM-1, TNF-α, and cleaved PARP-1 remained increased after Sirt6 knockdown. Conclusions: Endothelium-specific Sirt6 deletion promotes arterial thrombosis in mice. In cultured human aortic endothelial cells, SIRT6 silencing enhances TF expression and activates pro-inflammatory pathways including TNF-α, cleaved PARP-1, VCAM-1 and COX-2. Hence, endogenous endothelial SIRT6 exerts a protective role in experimental arterial thrombosis. Graphical abstract: Unlabelled Image Highlights: Loss of endothelial Sirt6 accelerates arterial thrombotic occlusion in vivo. SIRT6 knockdown increases TF expression and activity in aortic endothelial cells. SIRT6 knockdown activates pro-inflammatory cytokines in aortic endothelial cells.