Vasoactive prostanoids and redox signaling are integral to cardiovascular physiology and disease. Principal amongst these mediators are prostacyclin (PGI2), predominantly cyclooxygenase (COX)-2-derived, and thromboxane (TxA2), the primary product of platelet COX-1. Opposition of TxA2 by PGI2 appears critical to cardiovascular homeostasis and pathophysiology - depression of PGI2 generation, with unrestricted biosynthesis of TxA2 provides a mechanistic explanation for the cardiovascular risk associated with selective COX-2 inhibitors. Biosynthesis of TxA2 and PGI2, and expression of their receptors, is augmented coincident with elevated reactive oxygen species (ROS) in cardiovascular disease. The dynamic interplay between these prostanoids appears to be mediated by complex interactions of their receptors and signaling events that they transduce. This proposal will investigate novel pathways through which redox signaling modulates the regulation, function and dimeric association of the receptors for TxA2 (the TP) and PGI2 (the IP). These studies will provide novel mechanistic insights into human cardiovascular disease. We will examine the convergence of TP and IP on redox signaling in three specific aims.
Specific Aim 1 will define the mechanisms that drive a feed-froward loop, through which TP-derived ROS enhance TP expression, in vascular cells and in a mouse model of vascular injury.
In Specific Aim 2, we will examine how IP-dependent modulation of TP can interrupt this loop. Finally, in Specific Aim 3, we propose to examine non-monomeric association of TP and IP, and the role of ROS in this process, as a regulator of receptor expression and function. Relevance to public health: The cardiovascular system has a series of check and balances designed to keep it functioning and prevent disease. This work will investigate one such system, examining novel mechanisms through which one mediator, prostacyclin, works to offsets the actions of another thromboxane, thus contributing to the maintenance of cardiovascular health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066233-09
Application #
8090342
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Gao, Yunling
Project Start
2000-12-01
Project End
2012-12-30
Budget Start
2011-07-01
Budget End
2012-12-30
Support Year
9
Fiscal Year
2011
Total Cost
$354,375
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ibrahim, Salam; McCartney, Ann; Markosyan, Nune et al. (2013) Heterodimerization with the prostacyclin receptor triggers thromboxane receptor relocation to lipid rafts. Arterioscler Thromb Vasc Biol 33:60-6
Siangjong, Lawan; Gauthier, Kathryn M; Pfister, Sandra L et al. (2013) Endothelial 12(S)-HETE vasorelaxation is mediated by thromboxane receptor inhibition in mouse mesenteric arteries. Am J Physiol Heart Circ Physiol 304:H382-92
Frey, Alexander J; Ibrahim, Salam; Gleim, Scott et al. (2013) Biased suppression of TP homodimerization and signaling through disruption of a TM GxxxGxxxL helical interaction motif. J Lipid Res 54:1678-90
Yu, Ying; Stubbe, Jane; Ibrahim, Salam et al. (2010) Cyclooxygenase-2-dependent prostacyclin formation and blood pressure homeostasis: targeted exchange of cyclooxygenase isoforms in mice. Circ Res 106:337-45
Smyth, Emer M (2010) Thromboxane and the thromboxane receptor in cardiovascular disease. Clin Lipidol 5:209-219
Ibrahim, Salam; Tetruashvily, Mazell; Frey, Alex J et al. (2010) Dominant negative actions of human prostacyclin receptor variant through dimerization: implications for cardiovascular disease. Arterioscler Thromb Vasc Biol 30:1802-9
Smyth, Emer M; Grosser, Tilo; Wang, Miao et al. (2009) Prostanoids in health and disease. J Lipid Res 50 Suppl:S423-8
Wilson, Stephen J; Cavanagh, Claire C; Lesher, Allison M et al. (2009) Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species. J Lipid Res 50:1047-56
Wilson, Stephen J; McGinley, Kevin; Huang, Albert J et al. (2007) Heterodimerization of the alpha and beta isoforms of the human thromboxane receptor enhances isoprostane signaling. Biochem Biophys Res Commun 352:397-403
Wilson, Stephen J; Dowling, Jennifer K; Zhao, Lei et al. (2007) Regulation of thromboxane receptor trafficking through the prostacyclin receptor in vascular smooth muscle cells: role of receptor heterodimerization. Arterioscler Thromb Vasc Biol 27:290-6

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