Impact of the phosphatidylinositide 3-kinase signaling pathway on the cardioprotection induced by intermittent hypoxia.

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 8 Issue 10 Pg. e76659 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24124584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphatidylinositol 3-Kinases
• Vascular Endothelial Growth Factor Receptor-2
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Hemodynamics
• Hypoxia (metabolism)
• Male
• Mice
• Myocardial Contraction
• Myocardial Reperfusion Injury (metabolism, physiopathology)
• Myocardium (metabolism)
• Neovascularization, Physiologic
• Oxidative Stress
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)