Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system

Cardiovasc Res. 2021 Aug 29;117(10):2275-2288. doi: 10.1093/cvr/cvaa268.


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 ischaemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation.

Methods and results: Sirt5 transgenic (Sirt5Tg/0) and knock-out (Sirt5-/-) mice underwent photochemically induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) were treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells 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 wild-type 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 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 expressions 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.

Conclusion: 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.

Keywords: Arterial thrombosis; Cardiovascular disease; PAI-1; SIRT5; Sirtuin 5; Tissue factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Acute Coronary Syndrome / blood
  • Acute Coronary Syndrome / enzymology
  • Adult
  • Aged
  • Animals
  • Carotid Artery Injuries / blood
  • Carotid Artery Injuries / enzymology*
  • Carotid Artery Injuries / genetics
  • Carotid Artery Thrombosis / blood
  • Carotid Artery Thrombosis / enzymology*
  • Carotid Artery Thrombosis / genetics
  • Case-Control Studies
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / enzymology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibrinolysis*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Phosphorylation
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Sirtuins / genetics
  • Sirtuins / metabolism*


  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human
  • SIRT5 protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • AMP-Activated Protein Kinases
  • SIRT5 protein, human
  • Sirtuins