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ORIGINAL RESEARCH ARTICLE

Phosphodiesterase-5 Inhibition Abolishes Neuron Apoptosis Induced by Chronic Hypoxia Independently of Hypoxia-Inducible Factor-1 Signaling

Anna Caretti^*,, Paola Bianciardi^*, Raffaella Ronchi^*, Monica Fantacci^*, Marco Guazzi^* and Michele Samaja^*,1

^* Department of Medicine, Surgery and Dentistry, University of Milan, San Paolo Hospital, Milan, Italy; and Istituto Nazionale per le Ricerche Cardiovascolari, Bologna, Italy

To whom requests for reprints should be addressed at ¹ University of Milan, San Paolo Hospital, via di Rudinì 8 I-20142 Milan, Italy. E-mail: michele.samaja{at}unimi.it and michelesamaja{at}yahoo.it.

Exposure to hypoxia triggers a variety of adverse effects in the brain that arise from metabolic stress and induce neuron apoptosis. Overexpression of the hypoxia-inducible factor-1 (HIF-1) is believed to be a major candidate in orchestrating the cell’s defense against stress. To test the impact of HIF-1 on apoptosis during chronic hypoxia in vivo, we examined the protective effect of modulating the nitric oxide (NO)/cGMP pathway by sildenafil, a selective inhibitor of phosphodiesterase-5 (PDE-5). Male ICR/CD-1 mice were divided into 3 groups (n = 6/group): normoxic (21% O₂), hypoxic (9.5% O₂), and hypoxic with sildenafil (1.4-mg/kg intraperitoneal injections daily). At the end of the 8-day treatment period, the mice were euthanized and cerebral cortex biopsies were harvested for analyses. We found that sildenafil: (1) did not significantly alter the hypoxia-induced weight loss and hemoglobin increase, but did augment plasma nitrates+nitrites and the tissue content of cGMP and phosphorylated (P) NO synthase III; (2) reversed the hypoxia-induced neuron apoptosis (terminal deoxynucleotidyl transferase positivity and double-staining immunofluorescence, P = 0.009), presumably through increased bcl-2/Bax (P = 0.0005); and (3) did not affect HIF-1, but rather blunted the hypoxia-induced increase in P-ERK1/2 (P = 0.0002) and P-p38 (P = 0.004). We conclude that upregulating the NO/cGMP pathway by PDE-5 inhibition during hypoxia reduces neuron apoptosis, regardless of HIF-1, through an interaction involving ERK1/2 and p38.

Key Words: chronic hypoxia • hypoxia signaling • HIF-1 • NO • bcl-2