Roles of Prostaglandin I ₂ and Thromboxane A ₂ in Cardiac Ischemia-Reperfusion Injury

Abstract

Background-Prostaglandin (PG) I 2 and thromboxane (TX) A 2 , the most common prostanoids in the cardiovascular system, are produced abundantly during cardiac ischemia/reperfusion (I/R); their roles in I/R injury, however, remain undetermined. We intended to clarify these roles of PGI 2 and TXA 2 using mice lacking the PGI 2 receptor, IP Ϫ/Ϫ mice, or the TXA 2 receptor, TP Ϫ/Ϫ mice. Methods and Results-The left anterior descending coronary artery was occluded for 1 hour and then reperfused for 24hours. The size of myocardial infarct in IP Ϫ/Ϫ mice was significantly larger than that in wild-type mice, although the size of the area at risk was similar between the 2 groups of mice. In contrast, there was no such difference between TP

Investigation of the Mechanisms of G Protein: Effector Coupling by the Human and Mouse Prostacyclin Receptors

“…The actions of prostacyclin generally counteract those of thromboxane A 2 , and the relative levels of these two prostanoids regulate platelet/endothelium/vascular smooth muscle interactions (5). Prostacyclin is abundantly produced during cardiac ischemia/reperfusion, conferring a cytoprotective effect (6), and, from studies carried out in prostacyclin receptor-deficient mice, is known to exert a protective effect on cardiomyocytes independent of its effects on platelets and neutrophils (7). Perturbations in prostacyclin and/or prostacyclin receptor signaling have been implicated in the pathogenesis of conditions such as ischemic heart disease, atherosclerosis, renal failure, and systemic and pregnancyinduced hypertension (5, 8 -10).…”

Adenovirus-Encoded Hammerhead Ribozyme to PDGF A-Chain mRNA Inhibits Neointima Formation after Arterial Injury

“…Todaka et al [13]have shown that the transfer of a human PGI 2 synthase expression vector into rat carotid arteries increased the production of human PGI 2 in the vascular wall and significantly inhibited neointima formation after balloon injury. It is known that TXA 2 and its receptor are involved in the development of various vascular occlusive diseases, including coronary heart diseases, and TXA 2 receptor antagonists have been proposed as a promising therapy against neointima formation after balloon injury and myocardial ischemia/reperfusion injury [14, 15, 16]. Zucker et al [17]have demonstrated that thromboxane potentiates PDGF-induced growth responses in coronary artery SMC, suggesting an interaction between PDGF and thromboxane.…”

“…PGI 2 inhibits whereas TXA 2 stimulates neointima and thrombus formation after balloon injury [13, 14, 15, 16]. TXA 2 potentiates PDGF-induced growth responses in coronary artery SMC [17].…”

Prostacyclin, Atherothrombosis, and Cardiovascular Disease

“…Only recently has its important role in preventing atherosclerosis and subsequent thrombosis (leading to myocardial infarction, stroke) been appreciated [8,9]. Loss of PGI 2 signaling due to deletion of the prostacyclin receptor (IP-International Union of Pharmacology Receptor classification) increased propensities towards thrombosis [2], intimal hyperplasia, and restenosis [1], as well as reperfusion injury in mouse models [10]. Furthermore, the recent withdrawals of rofecoxib (Vioxx) and valdecoxib (Bextra) due to increased risk of cardiovascular events (e.g., myocardial infarction and thrombotic stroke, particularly in predisposed patients) [11] underscore the urgent need to further assess prostacyclin's role in cardiovascular disease.…”