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Thromb Haemost 2018; 118(11): 1982-1996
DOI: 10.1055/s-0038-1672206
Atherosclerosis and Ischaemic Disease
Georg Thieme Verlag KG Stuttgart · New York

Genetic Depletion of Thromboxane A2/Thromboxane-Prostanoid Receptor Signalling Prevents Microvascular Dysfunction in Ischaemia/Reperfusion Injury

Chih-Yao Chiang   *
1   Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
2   Department of Cardiovascular Surgery, Taipei City Hospital RenAi Branch, Taipei, Taiwan
,
Chen-Yen Chien   *
3   Mackay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
4   Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
,
Wei-Yin Qiou
1   Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
,
Christopher Chang
5   High School Division, Taipei American School, Taipei, Taiwan
,
I-Shing Yu
6   Laboratory of Animal Center, National Taiwan University College of Medicine, Taipei, Taiwan
,
Po-Yuan Chang   **
7   Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University College of Medicine, Taipei, Taiwan
,
Chiang-Ting Chien   **
1   Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
› Author Affiliations Funding This work was supported by grants MOST-102–2320-B-003–001-MY3 (Chiang-Ting Chien), MOST-106–2314-B-002 -156 -MY2 (Po-Yuan Chang) from the Ministry of Science and Technology, and a research fund from Taipei City Hospital (Chih-Yao Chiang).
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Publication History

09 February 2018

22 August 2018

Publication Date:
09 October 2018 (online)

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Abstract

Objective Activation of thromboxane A2 synthase (TXAS)/thromboxane A2 (TXA2)/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 TXA2 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 B2 (TXB2) and superoxide anions (O2 −) 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 FeCl3 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, TXB2, O2 − 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 FeCl3 stimulation.

Conclusion Inhibiting TXAS/TXA2/TP signalling confers microvascular protection against oxidative injury in both cardiac and mesenteric arteries.

Keywords

aspirin - ischaemia/reperfusion injury - thromboxane A2 - thromboxane A2 synthase - thromboxane prostanoid receptor

* Chih-Yao Chiang and Chen-Yen Chien contributed equally to this study.


** Po-Yuan Chang and Chiang-Ting Chien contributed equally to this study.


Supplementary Material

 

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