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G13 is an essential mediator of platelet activation in hemostasis and thrombosis

Nature Medicine volume 9, pages 1418–1422 (2003)Cite this article

Abstract

Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke1,2. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A2 (TXA2) activate receptors that are coupled to heterotrimeric G proteins1,3. Activation of platelets through these receptors involves signaling through Gq, Gi and Gz (refs. 4–6). However, the role and relative importance of G12 and G13, which are activated by various platelet stimuli7,8,9, are unclear. Here we show that lack of Gα13, but not Gα12, severely reduced the potency of thrombin, TXA2 and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Gα13 deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G13-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.

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Figure 1: Generation of Gna13flox allele and Cre-mediated recombination in mice.
Figure 2: Ex vivo analysis of wild-type and Gα12/Gα13-deficient platelets.
Figure 3: Ex vivo analysis of wild-type and Gα12/Gα13-deficient platelets.
Figure 4: In vivo analysis of hemostasis and thrombosis.

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Acknowledgements

We thank A. Rogatzki and A. Rippberger for expert technical help and B. Arnold for kind help with bone marrow transplantation experiments. This work was supported by the Deutsche Forschungsgemeinschaft and the Volkswagen Foundation.

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Author notes

  1. Marie-Pierre Gratacap

    Present address: INSERM, Unité 326, Hôpital Purpan, 31059, Toulouse Cedex, France

Authors and Affiliations

  1. Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany

    Alexandra Moers, Nina Wettschureck, Marie-Pierre Gratacap & Stefan Offermanns

  2. Vascular Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, 97078, Germany

    Bernhard Nieswandt, Sabine Grüner, Valerie Schulte & Barsom Aktas

  3. Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universität München, München, D-80636, Germany

    Steffen Massberg, Ildiko Konrad & Meinrad Gawaz

  4. Division of Biology 147-75, California Institute of Technology, Pasadena, 91125, California, USA

    Melvin I Simon

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Moers, A., Nieswandt, B., Massberg, S. et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat Med 9, 1418–1422 (2003). https://doi.org/10.1038/nm943

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