Fundamental studies form the basis for the elucidation of platelet abnormalities seen in certain diseases. Hyperlipoproteinemia is associated with a 8-fold increased risk for cardiovascular disease (CVD). One of the possible causes is the stimulation of platelets by LDL and oxidized LDL. The signaling pathways have been characterized clarifying receptors (R) involved (apoE-R 2’ or LRP8 for LDL; CD36 – Scavenger-R A for oxLDL), their signaling through p38MAPkinase to generate thromboxane A2 (with platelet activating properties) and their down-regulation by inhibitory receptors (e.g. PECAM-1) and Tyr phosphatases SHP1/2. Diabetes mellitus type II is an equally severe risk for CVD. Activation of the insulin-R has been studied in relation to association with insulin-R substrate (IRS-1) and the GTP-protein subunit Gi alpha2 in platelets and monocytes. The findings revealed suppression of aggregation and secretion (platelets) and up-regulation of Tissue Factor, the initiator of coagulation (monocytes and platelets) by insulin in cells from healthy individuals. In diabetics, these cells have become insulin-resistant resulting in a up-regulation of aggregation and secretion by platelets and coagulation initiation by monocytes, possibly explaining increased CVD risk.
General Aim
To clarify abnormalities in patients with hypo- and hyperactive platelets caused by dys-regulation of the platelet activating machinery.
On this project are working:
Dr. J.A. Korporaal, post-doc
Drs. J. Gerrits, Ph.D. student
Drs. E. Tournoy, M.D.
Ing. C.A. Koekman, research technician
Publications:
Korporaal, S.J.A., G. Gorter, H.J.M. van Rijn and J.W.N. Akkerman. Effect of oxidation on the platelet activating properties of Low Density Lipoprotein. Arteriosclerosis, Thrombosis and Vascular Biology 2005; 25: 1-7
Korporaal, S.J.A., M. van Eck, J. Adelmeijer, R. Out, M. Bezemer, T. Lisman, P.J. Lenting, T.J.C. van Berkel, and J.W.N. Akkerman. Platelet activation by oxidized low-density lipoprotein is mediated by CD36 - Scavenger Receptor A complex. Arteriosclerosis, Thrombosis and Vascular Biology 2007; 27: 2476-2483
Korporaal, S.J.A., C.A. Koekman, S. Verhoef, G. Gorter, M. Bezemer, M. van Eck and J.W.N. Akkerman. Down-regulation of LDL-induced platelet activation by the protein tyrosine phosphatases SHP1/2. .Arteriosclerosis, Thrombosis and Vascular Biology, Epub 2008, Nov
Gerrits, A. J., C. Yildirim and J.W.N. Akkerman. Regulation of tissue factor synthesis by insulin in monocytes. Journal of Thrombosis and Haemostasis 2008, Epub Oct 28
Akkerman, J.W.N., A.J. Gerrits, I. Andrade Ferreira and J.W.M. Heemskerk. Insulin inhibition of platelet-endothelial interaction is mediated by insulin effects on endothelial cells without direct effects on platelets. A rebuttal. Journal of Thrombosis and Haemostasis 2008, in press
Andrade Ferreira, I., A.I. Mocking, M.A.H. Feijge, G. Gorter, T.W. van Haeften, J.W. M. Heemskerk and J.W.N. Akkerman. Platelet Inhibition by Insulin Is Absent in Type 2 Diabetes Mellitus.
Arteriosclerosis, Thrombosis and Vascular Biology 2006; 26: 417-422