Page 176 - 2019_12-Haematologica-web

S.N. Chaurasia et al.
found upregulation of HIF-2a expression in platelets under hypoxic stress or upon exposure to hypoxia-mimet- ics, which stabilize HIF-2a by inhibiting prolyl hydroxy- lases. In parallel, we documented significantly higher PAI- 1 expression in platelets (Figure 3A, B, D, E), thus under- scoring the possibility of HIF-2a-mediated regulation of PAI-1 synthesis. EV shed by stimulated or stressed platelets31,32 are endowed with pro-coagulant properties, and play an important role in hemostatic responses.33,34 Remarkably, the release of PEV from platelets exposed to
hypoxia was enhanced by 1.5- to 3-fold compared to that from platelets in a normoxic environment (Figure 3C). Both synthesis of PAI-1 and release of EV by platelets con- tribute to a prevailing prothrombotic state in an organism in a hypoxic environment.
We next examined the effect of the hypoxia-mimetics DMOG and DFO on platelets in a normoxic environment. Each of these drugs induced significantly higher expres- sion of HIF-2a (Figure 4A, B) and triggered extensive shed- ding of EV from platelets (Figure 4C), which was compa-
AB
CD
E
GH
Figure 5. Platelets from patients with chronic obstructive pulmonary disease and from high altitude residents have higher expression of HIF-2a and PAI-1. (A, B, E, F) Immunoblotting against HIF-2a (A, E) and PAI-1 (B, F) in platelets obtained from patients with chronic obstructive pulmonary disease (COPD) (n=10) (A, B) and high- altitude residents (n=10) (E, F) along with respective controls (n=10). (C, D, G, H) Corresponding densitometric analyses normalized to β-actin. Data are represented as the mean ± standard error of mean of ten different experiments. *P<0.05; **P<0.01, analyzed by the Mann Whitney test.
2490
haematologica | 2019; 104(12)
F