TY - JOUR
T1 - Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia
AU - Milano, Giuseppina
AU - Abruzzo, Provvidenza Maria
AU - Bolotta, Alessandra
AU - Marini, Marina
AU - Terraneo, Laura
AU - Ravara, Barbara
AU - Gorza, Luisa
AU - Vitadello, Maurizio
AU - Burattini, Sabrina
AU - Curzi, Davide
AU - Falcieri, Elisabetta
AU - von Segesser, Ludwig K.
AU - Samaja, Michele
PY - 2013/10/4
Y1 - 2013/10/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84885028439&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885028439&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0076659
DO - 10.1371/journal.pone.0076659
M3 - Article
C2 - 24124584
AN - SCOPUS:84885028439
VL - 8
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e76659
ER -