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 (Sirt5(Tg/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, Sirt5(Tg/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-alpha. 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
