TY - JOUR
T1 - Genetic Depletion of Thromboxane A 2 /Thromboxane-Prostanoid Receptor Signalling Prevents Microvascular Dysfunction in Ischaemia/Reperfusion Injury
AU - Chiang, Chih Yao
AU - Chien, Chen Yen
AU - Qiou, Wei Yin
AU - Chang, Christopher
AU - Yu, I. Shing
AU - Chang, Po Yuan
AU - Chien, Chiang Ting
N1 - Publisher Copyright:
© 2018 Georg Thieme Verlag. All rights reserved.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - aspirin
KW - ischaemia/reperfusion injury
KW - thromboxane A
KW - thromboxane A synthase
KW - thromboxane prostanoid receptor
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U2 - 10.1055/s-0038-1672206
DO - 10.1055/s-0038-1672206
M3 - Article
C2 - 30300909
AN - SCOPUS:85055599702
SN - 0340-6245
VL - 118
SP - 1982
EP - 1996
JO - Thrombosis and Haemostasis
JF - Thrombosis and Haemostasis
IS - 11
ER -