Genetic Depletion of Thromboxane A 2 /Thromboxane-Prostanoid Receptor Signalling Prevents Microvascular Dysfunction in Ischaemia/Reperfusion Injury

Chih Yao Chiang, Chen Yen Chien, Wei Yin Qiou, Christopher Chang, I. Shing Yu, Po Yuan Chang, Chiang Ting Chien

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Abstract

Objective Activation of thromboxane A 2 synthase (TXAS)/thromboxane A 2 (TXA 2 )/thromboxane prostanoid (TP) receptor leads to arterial constriction, platelet aggregation and vascular injury. We attempted to characterize the microvascular dysfunction in ischaemia/reperfusion injury using genetically modified TXAS -/- , TP -/- and TXAS -/- TP -/- mice. Approach and Results The cardiac micro-circulation and electrocardiograms were evaluated from B6, TXAS -/- , TP -/- and TXAS -/- TP -/- mice in response to intravenous saline, endothelin-1, U46619 (a TXA 2 agonist) and myocardial ischaemia/reperfusion injury. Cardiac function was investigated with myocardial permeability, the troponin I concentration and the infarct size. Myocardial TXAS, TP, endothelial nitric oxide (NO) synthase (eNOS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOx4), 4-hydroxynonenal, interleukin (IL)-1β, cell apoptosis, coronary effluent thromboxane B 2 (TXB 2 ) and superoxide anions (O 2 - ) and NO concentrations were measured. Mice mesenteric reactivity in response to various drugs was assessed by wire myography. In vivo fluorescent platelet adhesiveness to the mesenteric arterial endothelium after FeCl 3 stimulation was examined. In B6 mice, ischaemia/reperfusion significantly increased levels of ST-segment elevation, myocardial TXAS, TP, NOx4, IL-1β, apoptosis, coronary endothelin-1, TXB 2 , O 2 - release and the infarct size, with concomitant decreases in eNOS, NO concentrations and cardiac micro-circulation. These effects were remarkably depressed in TXAS -/- , TP -/- and TXAS -/- TP -/- mice. Aspirin treatment or depletion of the TXAS, TP or TXAS/TP gene significantly attenuated the exaggerated vascular reactivity by vasoconstrictors and vasodilators and efficiently reduced platelet adhesion to the mesenteric endothelium under FeCl 3 stimulation. Conclusion Inhibiting TXAS/TXA 2 /TP signalling confers microvascular protection against oxidative injury in both cardiac and mesenteric arteries.

Original languageEnglish
Pages (from-to)1982-1996
Number of pages15
JournalThrombosis and Haemostasis
Volume118
Issue number11
DOIs
Publication statusPublished - 2018 Jan 1

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Keywords

  • aspirin
  • ischaemia/reperfusion injury
  • thromboxane A
  • thromboxane A synthase
  • thromboxane prostanoid receptor

ASJC Scopus subject areas

  • Hematology

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