Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of hypoxia-inducible factor-1α signaling

Anna Caretti, Paola Bianciardi, Raffaella Ronchi, Monica Fantacci, Marco Guazzi, Michele Samaja

Research output: Contribution to journalArticle

Abstract

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-1α (HIF-1α) is believed to be a major candidate in orchestrating the cell's defense against stress. To test the impact of HIF-1α 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-1α, 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-1α, through an interaction involving ERK1/2 and p38.

Original languageEnglish
Pages (from-to)1222-1230
Number of pages9
JournalExperimental Biology and Medicine
Volume233
Issue number10
DOIs
Publication statusPublished - Oct 2008

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Type 5 Cyclic Nucleotide Phosphodiesterases
Hypoxia-Inducible Factor 1
Neurons
Apoptosis
Nitric Oxide
Phosphodiesterase 5 Inhibitors
DNA Nucleotidylexotransferase
Biopsy
Nitrites
Nitric Oxide Synthase
Nitrates
Brain
Physiological Stress
Hemoglobins
Tissue
Intraperitoneal Injections
Plasmas
Cerebral Cortex
Fluorescent Antibody Technique
Hypoxia

Keywords

  • Bcl-2
  • Chronic hypoxia
  • HIF-lα
  • Hypoxia signaling
  • NO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of hypoxia-inducible factor-1α signaling. / Caretti, Anna; Bianciardi, Paola; Ronchi, Raffaella; Fantacci, Monica; Guazzi, Marco; Samaja, Michele.

In: Experimental Biology and Medicine, Vol. 233, No. 10, 10.2008, p. 1222-1230.

Research output: Contribution to journalArticle

Caretti, Anna ; Bianciardi, Paola ; Ronchi, Raffaella ; Fantacci, Monica ; Guazzi, Marco ; Samaja, Michele. / Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of hypoxia-inducible factor-1α signaling. In: Experimental Biology and Medicine. 2008 ; Vol. 233, No. 10. pp. 1222-1230.
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