Platelet activation plays critical roles in the development of thrombotic diseases such as heart attack and stroke. The roles of platelets in thrombosis involve two major aspects: Firstly, platelet adhesion, aggregation and secretion of granule contents are important in the development of atherosclerosis, which causes chronic vascular injury. Secondly, platelet activation at the site of vascular injury is critical in initiating arterial thrombosis. An intracellular secondary messenger molecule, cGMP, is synthesized during platelet activation. The role of cGMP in platelet activation has been controversial since the discovery of cGMP. It has been a prevailing concept in the past 30 years that cGMP, by activating the cGMP-dependent protein kinase (PKG), inhibits platelet activation. This concept, however, has been challenged by our recent finding that cGMP and PKG play a biphasic role in platelet activation, We show that cGMP plays a stimulatory role when low concentrations of cGMP is produced upon platelet agonist stimulation, but becomes inhibitory at high cGMP concentrations. During the last funding period, we have made significant progress in understanding the mechanisms of the biphasic roles of the cGMP pathway in platelet activation. We have found that the cGMP-PKG pathway plays a general role in stimulating platelet secretion and secretion-dependent platelet aggregation induced by most platelet agonists. We have obtained evidence supporting a new upstream signaling pathway of cGMP during platelet activation involving phosphoinositide 3-kinase, various forms of Akt and nitric oxide (NO) synthase. We have also obtained evidence supporting a novel downstream signaling mechanism of cGMP involving various isoforms of PKG and PKG-dependent sequentially activation of p38 and ERK mitogen-activated protein kinase pathways. These discoveries allow us to hypothesize a novel signaling pathway that stimulates platelet secretion. In this pathway, platelet agonists, by activating different isoforms of PI3K, Akt, NOS3, soluble guanylyl cyclase, and PKG, and via the p38 and ERK pathways, induce platelet secretion, which amplifies and stabilizes platelet aggregation. To test this hypothesis, we propose following specific aims: 1. To investigate the role of different Akt isoforms as upstream activators of the cGMP pathway during platelet activation. 2. To determine mechanisms of agonist-induced platelet NO production, its regulation, and its role in platelet secretion and aggregation. 3. To characterize the roles and the signaling mechanisms of different isoforms of PKG in platelet secretion and aggregation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068819-08
Application #
7617166
Study Section
Special Emphasis Panel (ZRG1-HEME-C (03))
Program Officer
Kindzelski, Andrei L
Project Start
2002-01-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
8
Fiscal Year
2009
Total Cost
$376,263
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Huang, Yunjie; Joshi, Smita; Xiang, Binggang et al. (2016) Arf6 controls platelet spreading and clot retraction via integrin ?IIb?3 trafficking. Blood 127:1459-67
Xiang, Binggang; Zhang, Guoying; Ye, Shaojing et al. (2015) Characterization of a Novel Integrin Binding Protein, VPS33B, Which Is Important for Platelet Activation and In Vivo Thrombosis and Hemostasis. Circulation 132:2334-44
Estevez, Brian; Stojanovic-Terpo, Aleksandra; Delaney, M Keegan et al. (2013) LIM kinase-1 selectively promotes glycoprotein Ib-IX-mediated TXA2 synthesis, platelet activation, and thrombosis. Blood 121:4586-94
Yin, Hong; Stojanovic-Terpo, Aleksandra; Xu, Weidong et al. (2013) Role for platelet glycoprotein Ib-IX and effects of its inhibition in endotoxemia-induced thrombosis, thrombocytopenia, and mortality. Arterioscler Thromb Vasc Biol 33:2529-37
Delaney, M Keegan; Liu, Junling; Zheng, Yi et al. (2012) The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation. Arterioscler Thromb Vasc Biol 32:2761-8
O'Brien, Kelly A; Gartner, T Kent; Hay, Nissim et al. (2012) ADP-stimulated activation of Akt during integrin outside-in signaling promotes platelet spreading by inhibiting glycogen synthase kinase-3?. Arterioscler Thromb Vasc Biol 32:2232-40
O'Brien, Kelly A; Stojanovic-Terpo, Aleksandra; Hay, Nissim et al. (2011) An important role for Akt3 in platelet activation and thrombosis. Blood 118:4215-23
Zhang, Guoying; Xiang, Binggang; Dong, Anping et al. (2011) Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation. Blood 118:3670-9
Li, Zhenyu; Zhang, Guoying; Liu, Junling et al. (2010) An important role of the SRC family kinase Lyn in stimulating platelet granule secretion. J Biol Chem 285:12559-70
Li, Zhenyu; Delaney, M Keegan; O'Brien, Kelly A et al. (2010) Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol 30:2341-9

Showing the most recent 10 out of 31 publications