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.
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