Abstract 20237: Genetic Depletion of Thromboxane A2/Thromboxane-Prostanoid Receptor Signaling Prevents Microvascular Dysfunction in Ischemia/Reperfusion Injury

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Introduction: Activation of thromboxane A2 synthase (TXAS)/thromboxane A2 (TXA2)/thromboxane-prostanoid receptor (TP) leads to arterial constriction, platelet aggregation and ultimate vascular damage. In this study, we aimed to characterize the microvascular dysfunction in ischemia/reperfusion injury using genetically modified TXAS-/- and TXAS-/-TP-/- mice.

Methods: Cardiac microcirculation and electrocardiogram were determined from B6, TXAS-/- and TXAS-/-TP-/- mice in response to intravenous saline, endothelin-1, U46619 (TXA2 agonist) or myocardial ischemia/reperfusion injury. Cardiac edema extravasation and troponin I concentration were also evaluated. Myocardial expression of TXAS, TP, eNOS, NADPH oxidase NOx4, 4-hydroxynonenal and IL-1β, TUNEL-apoptosis stain, and coronary effluent TXB2, O2- and NO were assessed. Mesenteric microcirculation was investigated by wire myograph of mesenteric artery from mice treated with norepinephrine, endothelin-1, U46619 or acetylcholine. In vivo fluorescent platelet adhesiveness to mesenteric arterial endothelium after FeCl3 stimulation was also examined.

Results: In B6 mice, myocardial ischemia/reperfusion significantly increased the expression of TXAS, TP, NOx4, coronary endothelin-1, TXB2 and O2- release. In contrast, the eNOS and NO concentration and cardiac microcirculation were reduced. These effects were remarkably inhibited by aspirin. In TXAS-/- and TXAS-/-TP-/- mice, depletion of TXAS or TXAS/TP gene attenuated norepinephrine-, U46619- or endothelin-1-induced vasoconstriction, and enhanced low-dose acetylcholine-mediated vasodilation. These TXAS and TXAS/TP-deficient mice revealed marked decrease in oxidative and pro-inflammatory markers after ischemia/reperfusion injury. Pathology also demonstrated a decrease in the infarct size, with mitigation of platelet adhesion to the mesenteric endothelium.

Conclusions: Inhibiting TXAS/TXA2/TP signaling confers vascular protection against ischemia/reperfusion injury in both cardiac and mesenteric arteries. Attenuation of mesenteric microvascular dysfunction by aspirin also suggests a role of antiplatelet agents in the prevention of ischemic bowel diseases.

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