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 A
2
- thromboxane A
2 synthase - thromboxane prostanoid receptor