Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

Giuseppina Milano, Provvidenza Maria Abruzzo, Alessandra Bolotta, Marina Marini, Laura Terraneo, Barbara Ravara, Luisa Gorza, Maurizio Vitadello, Sabrina Burattini, Davide Curzi, Elisabetta Falcieri, Ludwig K. von Segesser, Michele Samaja

Research output: Contribution to journalArticle

Abstract

Background:Exposure to intermittent hypoxia (IH) may enhance cardiac function and protects heart against ischemia-reperfusion (I/R) injury. To elucidate the underlying mechanisms, we developed a cardioprotective IH model that was characterized at hemodynamic, biochemical and molecular levels.Methods:Mice were exposed to 4 daily IH cycles (each composed of 2-min at 6-8% O2 followed by 3-min reoxygenation for 5 times) for 14 days, with normoxic mice as controls. Mice were then anesthetized and subdivided in various subgroups for analysis of contractility (pressure-volume loop), morphology, biochemistry or resistance to I/R (30-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion and measurement of the area at risk and infarct size). In some mice, the phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin was administered (24 μg/kg ip) 15 min before LAD.Results:We found that IH did not induce myocardial hypertrophy; rather both contractility and cardiac function improved with greater number of capillaries per unit volume and greater expression of VEGF-R2, but not of VEGF. Besides increasing the phosphorylation of protein kinase B (Akt) and the endothelial isoform of NO synthase with respect to control, IH reduced the infarct size and post-LAD proteins carbonylation, index of oxidative damage. Administration of wortmannin reduced the level of Akt phosphorylation and worsened the infarct size.Conclusion:We conclude that the PI3K/Akt pathway is crucial for IH-induced cardioprotection and may represent a viable target to reduce myocardial I/R injury.

Original languageEnglish
Article numbere76659
JournalPLoS One
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 4 2013

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Milano, G., Abruzzo, P. M., Bolotta, A., Marini, M., Terraneo, L., Ravara, B., Gorza, L., Vitadello, M., Burattini, S., Curzi, D., Falcieri, E., von Segesser, L. K., & Samaja, M. (2013). Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia. PLoS One, 8(10), [e76659]. https://doi.org/10.1371/journal.pone.0076659