Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex.
An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation is a major cause of acute coronary events and leptin was shown previously to facilitate ADP-induced platelet aggregation, we chose to define the signaling events involved in leptin-mediated platelet activation. Using pharmacological, biochemical, and cell biological approaches, we show that leptin-induced platelet activation required activation of a signaling cascade that included the long form of the leptin receptor, three kinases [Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt)], the insulin receptor substrate-1 (IRS-1), and the major human platelet cAMP phosphodiesterase phosphodiesterase 3A (PDE3A). Moreover, we identify a role for an intraplatelet LEPR/JAK2/IRS-1/PI3K/PKB/PDE3A molecular complex that allows for the selective leptin-mediated activation of platelets. Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease.
Elbatarny
Hisham S
HS
Dept. of Pharmacology & Toxicology, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Maurice
Donald H
DH
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000008:administration & dosage / Q000378:metabolism*; D054411:Receptors, Leptin; D015398:Signal Transduction / Q000502:physiology*
C515448:LEPR protein, human; D020738:Leptin; D009097:Multienzyme Complexes; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human