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Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity


Gaul, Daniel S; Weber, Julien; Van Tits, Lambertus J; Sluka, Susanna; Pasterk, Lisa; Reiner, Martin F; Calatayud, Natacha; Lohmann, Christine; Klingenberg, Roland; Pahla, Jürgen; Vdovenko, Daria; Tanner, Felix C; Camici, Giovanni G; Eriksson, Urs; Auwerx, Johan; Mach, François; Windecker, Stephan; Rodondi, Nicolas; L Uuml Scher, Thomas F; Winnik, Stephan; Matter, Christian M (2018). Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity. Cardiovascular Research, 114(8):1178-1188.

Abstract

BACKGROUND: Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI).
Methods and Results: Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3-/- mice (n = 6) was reduced by half compared to Sirt3+/+ wildtype (WT, n = 8, p<0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry (ROTEM) revealed accelerated clot formation and increased clot stability in Sirt3-/- compared to WT blood. ROTEM of cell-depleted plasma showed accelerated clotting initiation in Sirt3-/- mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap (NET) formation was increased in Sirt3-/- bone marrow (BM)-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3-/- mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in BM-derived Sirt3-/- neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, p<0.01).
CONCLUSIONS: Sirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of NETs and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.

Abstract

BACKGROUND: Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI).
Methods and Results: Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3-/- mice (n = 6) was reduced by half compared to Sirt3+/+ wildtype (WT, n = 8, p<0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry (ROTEM) revealed accelerated clot formation and increased clot stability in Sirt3-/- compared to WT blood. ROTEM of cell-depleted plasma showed accelerated clotting initiation in Sirt3-/- mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap (NET) formation was increased in Sirt3-/- bone marrow (BM)-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3-/- mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in BM-derived Sirt3-/- neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, p<0.01).
CONCLUSIONS: Sirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of NETs and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Physiology (medical), Physiology, Cardiology and Cardiovascular Medicine
Language:English
Date:10 February 2018
Deposited On:15 Mar 2018 20:04
Last Modified:19 Aug 2018 15:08
Publisher:Oxford University Press
ISSN:0008-6363
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cvr/cvy036
PubMed ID:29444200

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