Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system
| Autor: | Frank Ruschitzka, Kimon Stamatelopoulos, Luca Liberale, Giovanni G. Camici, Melroy X. Miranda, Nicole R. Bonetti, Vanasa Nageswaran, Konstantinos Stellos, Francesco Paneni, Jürg H. Beer, Alexander Akhmedov, Nikolaos I. Vlachogiannis, Fabrizio Montecucco, Thomas F. Lüscher, Sarah Costantino, Yustina M. Puspitasari, Lena Schwarz |
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| Přispěvatelé: | University of Zurich |
| Rok vydání: | 2021 |
| Předmět: |
Male
Physiology medicine.medical_treatment PAI-1 030204 cardiovascular system & hematology Pharmacology arterial thrombosis AMP-Activated Protein Kinases chemistry.chemical_compound 0302 clinical medicine cardiovascular disease Sirtuin 5 Sirtuins Platelet Phosphorylation Extracellular Signal-Regulated MAP Kinases Cells Cultured Mice Knockout 0303 health sciences biology Fibrinolysis Middle Aged Thrombosis 3. Good health medicine.anatomical_structure Plasminogen activator inhibitor-1 Sirtuin 10209 Clinic for Cardiology Female Cardiology and Cardiovascular Medicine SIRT5 tissue factor Adult Endothelium 610 Medicine & health 03 medical and health sciences Physiology (medical) Plasminogen Activator Inhibitor 1 medicine Animals Humans Carotid Artery Thrombosis Thrombus Acute Coronary Syndrome 030304 developmental biology Aged business.industry Endothelial Cells medicine.disease Mice Inbred C57BL Disease Models Animal chemistry Case-Control Studies biology.protein business Carotid Artery Injuries Plasminogen activator |
| DOI: | 10.5167/uzh-201100 |
| Popis: | AIMS Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation. METHODS AND RESULTS Sirt5 transgenic (Sirt5Tg/0) as well as knock-out (Sirt5-/-) mice underwent photochemically-induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells (PBMCs) from acute coronary syndrome (ACS) patients and non-ACS controls (case-control study, total n = 171) were used to increase the translational relevance of our data. Compared to WT controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5-/-mice arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor (TFPI) expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5-/- mice. Accordingly, Sirt5-/- mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expression are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5. CONCLUSIONS SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events. TRANSLATIONAL PERSPECTIVES This study illustrates a novel role for Sirtuin 5 in arterial thrombosis by regulating fibrinolysis through plasminogen activator inhibitor 1 (PAI-1). These results shed new light onto the pathophysiology of arterial thrombus formation which underlies most of the acute atherosclerotic complications. Also, they further affirm the intrinsic relationship between lifespan regulating genes, vascular dysfunction and age-related cardiovascular disease, thus indicating these genes as potential targets for cardiovascular prevention and therapy. Further studies will be needed to assess the predictive ability of SIRT5 in patients with acute cardiovascular or cerebrovascular events. Also, the design of specific SIRT5 inhibitors will allow trials aiming at investigating the efficacy of SIRT5 blockage in the clinical setting. |
| Databáze: | OpenAIRE |
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