Leptin signalling and leptin-mediated activation of human platelets: importance of JAK2 and the phospholipases Cgamma2 and A2.
Leptin enhances agonist-induced platelet aggregation, and human platelets have been reported to express the leptin receptor. However, the pathways and mediators lying downstream of leptin binding to platelets remain, with few exceptions, unknown. In the present study, we sought to gain further insight into the possible role of leptin as a platelet agonist. Stimulation of platelets with leptin promoted thromboxane generation and activation of alpha(IIb)beta(3), as demonstrated by PAC-1 binding. Furthermore, it increased the adhesion to immobilised fibrinogen (p<0.001) and induced cytoskeletal rearrangement of both platelets and Meg01 cells. Leptin time- and dose-dependently phosphorylated the intracellular signalling molecules JAK2 and STAT3, although the importance of STAT3 for leptin-induced platelet activation remains to be determined. Important intracellular mediators and pathways activated by leptin downstream of JAK2 were found to include phosphatidylinositol-3 kinase, phospholipase Cgamma2 and protein kinase C, as well as the p38 MAP kinase-phospholipase A(2) axis. Accordingly, incubation with the specific inhibitors AG490, Ly294002, U73122, and SB203580 prevented leptin-mediated platelet activation. These results help delineate biologically relevant leptin signalling pathways in platelets and may improve our understanding of the mechanisms linking hyperleptinaemia to the increased thrombosis risk in human obesity.
Dellas
Claudia
C
Department of Cardiology and Pulmonary Medicine, Georg August University School of Medicine, 37099 Goettingen, Germany.
Schäfer
Katrin
K
Rohm
Ilonka K
IK
Lankeit
Mareike
M
Leifheit
Maren
M
Loskutoff
David J
DJ
Hasenfuss
Gerd
G
Konstantinides
Stavros V
SV
D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D051966:Phospholipase C gamma / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*
D020738:Leptin; D005340:Fibrinogen; D053614:Janus Kinase 2; D054467:Phospholipases A2; D051966:Phospholipase C gamma