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 #
5R01HL077213-09
Application #
8432820
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
2013-03-01
Budget End
2014-02-28
Support Year
9
Fiscal Year
2013
Total Cost
$332,931
Indirect Cost
$120,873
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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
Zimman, Alejandro; Titz, Bjoern; Komisopoulou, Evangelia et al. (2014) Phosphoproteomic analysis of platelets activated by pro-thrombotic oxidized phospholipids and thrombin. PLoS One 9:e84488
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
Panigrahi, Soumya; Ma, Yi; Hong, Li et al. (2013) Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res 112:103-12
Ding, Liang; Biswas, Sudipta; Morton, Richard E et al. (2012) Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis in mice. Cell Metab 15:861-72
Zhao, Yongzhong; Malinin, Nikolay L; Meller, Julia et al. (2012) Regulation of cell adhesion and migration by Kindlin-3 cleavage by calpain. J Biol Chem 287:40012-20
Somanath, Payaningal R; Podrez, Eugene A; Chen, Juhua et al. (2011) Deficiency in core circadian protein Bmal1 is associated with a prothrombotic and vascular phenotype. J Cell Physiol 226:132-40
West, Xiaoxia Z; Malinin, Nikolay L; Merkulova, Alona A et al. (2010) Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467:972-6
Ma, Yi; Ashraf, Mohammad Z; Podrez, Eugene A (2010) Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia. Blood 116:1932-41

Showing the most recent 10 out of 21 publications