Abstract Number: VPB0903
Meeting: ISTH 2022 Congress
Theme: Platelets and Megakaryocytes » Platelet Function and Interactions
Background: Some MMPs are regulators of platelet function. Platelets express and release MMP-2 that enhances platelet aggregation by cleaving PAR1 at a non conventional site. Atherosclerotic plaques are rich in MMP-13 that is also known to cleave PAR1 of cardiac cells. No studies however have explored whether MMP-13 can activate platelets.
Aims: Our aim was to explore the effect of MMP-13 on platelet PAR1, in vitro platelet activation and signal transduction, and to assess whether it modulates in vivo platelet-mediated thrombosis.
Methods: The cleavage site of PAR1 by rhMMP-13 was characterized using CHO cells transfected with pcDEF3/PAR1 T7- tagged human PAR-1; platelet function was assessed by flow-cytometry; in vivo hemostasis in mice by the tail tip-transection bleeding time; in vivo arterial thrombosis by a photochemical-injury femoral artery thrombosis model.
Results: MMP-13 cleave PAR1 on CHO cells, a reaction blocked by the antibody SPAN12 directed against the PAR1 N-terminal residues 35-46. Active MMP-13 potentiated ADP-induced human platelet P-selectin expression and platelet/leukocyte aggregate formation and triggered platelet G protein activation, effects abolished by WAY170523c (MMP-13 inhibitor) and by the blockade of platelet PAR1 by SPAN12. The ex vivo formation of platelet/monocyte aggregates, and, to a lesser extent platelet/neutrophil aggregates were reduced in MMP-13-/-mice as compared with WT mice suggesting that endogenous MMP-13 plays a role in platelet activation. Femoral artery thrombosis was significantly delayed (27±1.4 vs 11.5±1.7 min, respectively, P < 0.01) and the tail tip transection bleeding time was mildly, but significantly prolonged (390±76 vs 120±11 sec, P < 0.0001) in MMP-13-/- mice as compared to WT mice.
Conclusion(s): Our data data show that active MMP-13 activates platelets by cleaving PAR1 at a non canonical site. MMP-13 plays a role in in vivo platelet activation and thrombus formation at a vessel wall-injury site. MMP-13 represents a novel modulator of platelet function and a potential target of antithrombotic therapy.
To cite this abstract in AMA style:
Momi S, Sebastiano M, Falcinelli E, Gresele P. Matrix metalloproteinase-13: a novel player of platelet activation and in vivo thrombus formation [abstract]. https://abstracts.isth.org/abstract/matrix-metalloproteinase-13-a-novel-player-of-platelet-activation-and-in-vivo-thrombus-formation/. Accessed September 29, 2023.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/matrix-metalloproteinase-13-a-novel-player-of-platelet-activation-and-in-vivo-thrombus-formation/