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Novel Agonists and Antagonists of Platelet Receptors

På svenska

Author

  • Carl Högberg

Summary, in English

Platelets are central for the primary haemostatis. The platelet has surface bound receptors that are vital for the platelet activation. One of these receptors, the purinergic ADP-activated G-protein coupled receptor (GPCR) P2Y12 is a key receptor for platelet activation, and thus for thrombus formation, which makes P2Y12 a target in pharmaceutical antiplatelet therapies. As a complement during revascularization surgery, mild hypothermia has been accepted, but its effect on platelet activation is unclear. We performed a comparative ex vivo study on platelets, treated with mild hypothermia and normothermia in the presence of P2Y12 inhibitors. We found that mild hypothermia increased platelet P2Y12 activation and that the P2Y12 inhibitor, clopidogrel, lost in efficiency. The P2Y12 receptor is also present on vascular smooth muscle cells (VSMC), promoting contractions. We initiated a comparative study on human and murine artery tissue to evaluate if any of the antiplatelet substances, clopidogrel and ticagrelor (AZD6140) a reversibly non-prodrug P2Y12 inhibitor, could inhibit P2Y12 signaling also on VSMC. The results showed that ticagrelor was able to inhibit P2Y12 stimulated vasoconstriction, while clopidogrel had no effect. The succinate GPCR (SUCNR1) mRNA has been found at high levels in platelets. We performed a study on SUCNR1 to investigate its function in platelets. The study showed that the succinate receptor was expressed as a membrane bound Gαi-protein. Succinate per se could mediate platelet activation. It was dependent on P2Y12 activation, tromboxane A2 release and PI3Kβ signaling. By screening intermediates in the mevalonate pathway, i.e. the cholesterol synthesis, we found that one of them, farnesyl pyrophosphate (FPP), had an antagonistic effect on ADP induced platelet activation. Further investigation on FPP with [35S]GTPγS binding and docking studies confirmed that FPP is an endogenous antagonist on the platelet P2Y12 receptor.

Department/s

Publishing year

2011

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

2011:3

Document type

Dissertation

Publisher

Department of Cardiology, Clinical sciences, Lund University

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • Platelets
  • P2Y12
  • SUCNR1
  • FPP
  • hypothermia

Status

Published

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-86671-53-2

Defence date

14 January 2011

Defence time

09:00

Defence place

Segerfalksalen,Wallenberg neurocentrum, BMC, Sölvegatan 17, Lund

Opponent

  • Torbjörn Bengtsson (Professor)