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The S1P2 receptor expressed in human platelets is linked to the RhoA-Rho kinase pathway and is down regulated in type 2 diabetes

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Abstract

Sphingosine-1-phosphate (S1P) is known to affect platelet responsiveness but the receptor mediating these effects and the mechanisms involved are poorly understood. This study was undertaken to examine S1P receptor expression in human platelets as well as potential changes associated with type 2 diabetes. S1P2 receptor expression (Western blotting) was detected in washed human platelets from healthy volunteers. Stimulation of these platelets with exogenous S1P led to a concentration-dependent increase in intracellular Ca2+ as well as to platelet aggregation. The S1P-induced increase in Ca2+ was sensitive to the S1P2 receptor antagonist JTE-013 but not the S1P1/3 antagonist VPC23019. Both antagonists reduced the aggregation stimulated by S1P in a non-additive manner. S1P also elicited the translocation of RhoA to the membrane and RhoA activity was inhibited (by 50%) by the S1P receptor antagonists. Platelets from patients with type 2 diabetes demonstrated an attenuated aggregability to S1P as well as decreased levels of the full-length S1P2 protein. The S1P2 antibody used identified a 45 kDa receptor cleavage product in patients with diabetes that could also be generated from healthy human platelet lysates by the addition of the Ca2+-activated protease, μ-calpain. These results indicate that the S1P2 receptor is involved in S1P-induced platelet aggregation and Rho kinase activation. Moreover, in platelets from patients with type 2 diabetes, responses to S1P are attenuated via a phenomenon attributed to the calpain-dependent cleavage of the S1P2 receptor.

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Acknowledgments

The authors are indebted to Katharina Bruch and Claudia Grosser for expert technical assistance. The experimental work described in this manuscript was supported by the Deutsche Forschungsgemeinschaft (SFB 533, B5; and by Exzellenzcluster 147 “Cardio-Pulmonary Systems”) as well as by the Lipid Signaling Research Center Frankfurt and a young investigator grant (to VR) awarded by the Medical faculty of the Goethe University, Frankfurt.

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Authors and Affiliations

  1. Institut für Vascular Signalling, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Voahanginirina Randriamboavonjy, Beate Fisslthaler & Ingrid Fleming PhD

  2. Dept. of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

    Klaus Badenhoop

  3. Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

    Helmut Schmidt & Gerd Geisslinger

Authors
  1. Voahanginirina Randriamboavonjy
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  2. Klaus Badenhoop
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  3. Helmut Schmidt
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  4. Gerd Geisslinger
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  5. Beate Fisslthaler
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Correspondence to Ingrid Fleming PhD.

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Returned for 1. Revision: 27 August 2008 1. Revision received: 11 September 2008

Returned for 2. Revision: 26 September 2008 2. Revision received: 6 November 2008

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Randriamboavonjy, V., Badenhoop, K., Schmidt, H. et al. The S1P2 receptor expressed in human platelets is linked to the RhoA-Rho kinase pathway and is down regulated in type 2 diabetes. Basic Res Cardiol 104, 333–340 (2009). https://doi.org/10.1007/s00395-008-0769-1

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  • DOI: https://doi.org/10.1007/s00395-008-0769-1

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