A significant role for increased platelet reactivity in the pathophysiology of occlusive arterial thrombosis is widely recognized. However, the mechanisms responsible for enhancing platelet reactivity in vivo during hyperlipidemia are poorly understood. We have recently isolated and structurally defined a novel family of oxidized choline glycerophospholipids (oxPCCD36) that are present in vivo at sites of enhanced oxidative stress. oxPCCD36 serve as high affinity ligands for scavenger receptors class B and modulate platelet reactivity and thrombosis in oxidative stress. Our preliminary studies demonstrated that a class of products formed as a result of degradation of oxPCCD36 by PLA2 (carboxyalkylpyrolle protein adducts) is a new and powerful platelet agonist, however, the receptors mediating its effect are not known. Platelets express a number of receptors with pattern recognition properties, including several toll like receptors (TLRs). A recent study suggested that platelet TLRs may modulate thrombosis when their ligands are present in circulation. This proposal will address the hypothesis that platelet TLRs alone, or in cooperation with scavenger receptors modulate platelet reactivity and prothrombotic state induced by endogenous ligands generated in oxidative stress. This proposal will also pursue the hypothesis that carboxyalkylpyrolle protein adducts serve as novel ligands for platelet scavenger /toll like receptors and identify the mechanisms of prothrombotic activity. Finally, we will continue the investigation of the molecular mechanism of scavenger receptor BI regulation of platelet function and thrombosis in dyslipidemia. Our preliminary data strongly support our hypothesis.
The Specific Aims are:
Aim1 : To assess whether the platelet activating and prothrombotic activities of oxPCCD36 are mediated by platelet TLRs alone, or in cooperation with scavenger receptors class B.
Aim2 : To investigate the role of scavenger receptor-BI in platelet function in dyslipidemia and oxidative stress.
Aim3 : To elucidate the mechanism and assess the physiological and pathophysiological consequences of the interaction between carboxyalkylpyrolle protein adducts (CAPs) and platelets.

Public Health Relevance

Risk for platelet-mediated blood clotting is increased in atherosclerotic disease; however, the mechanisms are poorly understood. We have recently demonstrated that specific oxidized phospholipids can control platelet function via platelet receptors. In this proposal we will study how platelet toll like receptors regulate platelet function and thrombosis in atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077213-08
Application #
8235849
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2004-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
8
Fiscal Year
2012
Total Cost
$349,718
Indirect Cost
$126,968
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Gao, Detao; Podrez, Eugene A (2018) Characterization of covalent modifications of HDL apoproteins by endogenous oxidized phospholipids. Free Radic Biol Med 115:57-67
Yakubenko, Valentin P; Cui, Kui; Ardell, Christopher L et al. (2018) Oxidative modifications of extracellular matrix promote the second wave of inflammation via ?2 integrins. Blood 132:78-88
Biswas, Sudipta; Zimman, Alejandro; Gao, Detao et al. (2017) TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia. Circ Res 121:951-962
Feng, Weiyi; Valiyaveettil, Manojkumar; Dudiki, Tejasvi et al. (2017) ?3 phosphorylation of platelet ?IIb?3 is crucial for stability of arterial thrombus and microparticle formation in vivo. Thromb J 15:22
Ding, Liang; Zhang, Lifang; Biswas, Sudipta et al. (2017) Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling JCI Insight 2:
Ding, Liang; Zhang, Lifang; Kim, Michael et al. (2017) Akt3 kinase suppresses pinocytosis of low-density lipoprotein by macrophages via a novel WNK/SGK1/Cdc42 protein pathway. J Biol Chem 292:9283-9293
Podrez, Eugene A; Byzova, Tatiana V (2016) Prothrombotic lipoprotein patterns in stroke. Blood 127:1221-2
Biswas, Sudipta; Xin, Liang; Panigrahi, Soumya et al. (2016) Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE-/- mice and activate platelets via TLR2. Blood 127:2618-29
Kim, Young-Woong; Yakubenko, Valentin P; West, Xiaoxia Z et al. (2015) Receptor-Mediated Mechanism Controlling Tissue Levels of Bioactive Lipid Oxidation Products. Circ Res 117:321-32
Gao, Detao; Willard, Belinda; Podrez, Eugene A (2014) Analysis of covalent modifications of proteins by oxidized phospholipids using a novel method of peptide enrichment. Anal Chem 86:1254-62

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