Endothelial SIRT6 deficiency promotes arterial thrombosis in mice.

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 Sirt6fl/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.

• Authors: Daniel S Gaul, Natacha Calatayud, Jürgen Pahla, Nicole R Bonetti, Yu-Jen Wang, Julien Weber, Samuele Ambrosini, Luca Liberale, Sarah Costantino, Shafeeq A Mohammed, Simon Kraler, Lambertus J Van Tits, Lisa Pasterk, Daria Vdovenko, Alexander Akhmedov, Frank Ruschitzka, Francesco Paneni, Thomas F Lüscher, Giovanni G Camici, Christian M Matter
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 174 Pg. 56-62 (01 2023) ISSN: 1095-8584 [Electronic] England
• PMID: 36414111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier Ltd.

Chemical References

• Cyclooxygenase 2
• NF-kappa B
• Poly(ADP-ribose) Polymerase Inhibitors
• Sirt6 protein, mouse
• Sirtuins
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1

Topics

• Animals
• Humans
• Male
• Mice
• Cells, Cultured
• Cyclooxygenase 2
• Endothelial Cells
• NF-kappa B
• Poly(ADP-ribose) Polymerase Inhibitors
• Sirtuins (genetics)
• Thrombosis (genetics)
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1 (genetics)