Page 185 - 2019_04-Haematologica-web

Aerobic glycolysis fuels platelet activation
to aerobic glycolysis and the PPP in stimulated platelets cause profound impairment of arterial thrombosis in vivo.
We corroborated the above findings in a mouse model of collagen-epinephrine-induced pulmonary embolism. Mice were pretreated with DCA (200 mg/kg), DHEA (50 mg/kg), DASA (40 mg/kg) or vehicle (control), followed
by intravenous administration of a collagen-epinephrine mixture to induce pulmonary embolism. Hematoxylin & eosin-stained lung sections from mice pretreated with small-molecule inhibitors displayed significantly fewer thrombosed pulmonary vessels [DCA, 4.12 ± 1.4 per low power field (lpf); DHEA, 4.02 ± 0.82/lpf; DASA, 3.03 ±
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C
D
E
Figure 4. Small-molecule inhibitors of aerobic glycolysis and the pentose phosphate pathway impair thrombus formation in mice. (A) Representative time lapse images exhibiting thrombus formation in mice, pre-administered either vehicle (control), DCA, DHEA, or DASA captured 5, 10 or 15 min after injury of mesenteric arte- rioles of >100 mm diameter with ferric chloride. (B and E) Scatter dot plots representing, respectively, time to first thrombus formation and time to stable occlusion in mice pre-administered vehicle (control), DCA, DHEA or DASA. (C and D) Line graph and bar diagram showing thrombus growth rate in different treatment groups, as indicated. Each dot in the scatter plots represents an independent observation. Data are expressed as the mean ± standard error of mean. *P<0.05 with respect to vehicle-treated mice. DASA: diarylsulfonamide; DCA: dichloroacetate; DHEA: dehydroepiandrosterone sulphate.
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