HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/E695    most recent 00125.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Elbatarny, H. S. Articles by Maurice, D. H. Search for Related Content PubMed PubMed Citation Articles by Elbatarny, H. S. Articles by Maurice, D. H.

Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex

Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada

Submitted 18 March 2005 ; accepted in final form 5 May 2005

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.

cyclic adenosine 3',5'-monophosphate; aggregation; adhesion; signaling

This article has been cited by other articles:

				P. F. Bodary Links Between Adipose Tissue and Thrombosis in the Mouse Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2284 - 2291. [Abstract] [Full Text] [PDF]

				W. Zhang and R. W. Colman Thrombin regulates intracellular cyclic AMP concentration in human platelets through phosphorylation/activation of phosphodiesterase 3A Blood, September 1, 2007; 110(5): 1475 - 1482. [Abstract] [Full Text] [PDF]

				M. Othman, A. Labelle, I. Mazzetti, H. S. Elbatarny, and D. Lillicrap Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance Blood, April 1, 2007; 109(7): 2832 - 2839. [Abstract] [Full Text] [PDF]