Genetic Depletion of Thromboxane A2/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

doi:10.1055/s-0038-1672206

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

Authors

Chih-Yao Chiang^*

¹Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

²Department of Cardiovascular Surgery, Taipei City Hospital RenAi Branch, Taipei, Taiwan
Chen-Yen Chien^*

³Mackay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan

⁴Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
Wei-Yin Qiou

¹Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
Christopher Chang

⁵High School Division, Taipei American School, Taipei, Taiwan
I-Shing Yu

⁶Laboratory of Animal Center, National Taiwan University College of Medicine, Taipei, Taiwan
Po-Yuan Chang^**

⁷Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University College of Medicine, Taipei, Taiwan
Chiang-Ting Chien^**

¹Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

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

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