Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ; Laboratorio di Biologia Vascolare e Medicina Regenerativa, Centro Cardiologico Monzino, IRCSS, Milan, Italy.
PLoS One. 2013 Oct 4;8(10):e76659. doi: 10.1371/journal.pone.0076659. eCollection 2013.
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.
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.
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.
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.
间歇性低氧（IH）暴露可能增强心脏功能并保护心脏免受缺血再灌注（I / R）损伤。为了阐明潜在的机制，我们开发了一种心脏保护的 IH 模型，该模型在血流动力学、生化和分子水平上进行了特征描述。
将小鼠暴露于 4 个每日 IH 周期（每个周期由 2 分钟 6-8%O2 组成，随后再氧合 3 分钟 5 次），共 14 天，以常氧小鼠作为对照。然后将小鼠麻醉并分为多个亚组进行分析，包括收缩性（压力-容积环）、形态学、生化或对 I / R 的抗性（左前降支冠状动脉（LAD）闭塞 30 分钟，随后再灌注和测量危险区和梗塞面积）。在一些小鼠中，在 LAD 前 15 分钟给予磷脂酰肌醇 3-激酶（PI3K）抑制剂渥曼青霉素（24μg/kg ip）。
我们发现 IH 不会引起心肌肥大；相反，随着单位体积毛细血管数量的增加以及 VEGF-R2 的表达增加（而不是 VEGF），收缩性和心脏功能都得到了改善。除了与对照组相比增加了蛋白激酶 B（Akt）和内皮型一氧化氮合酶的磷酸化外，IH 还降低了梗塞面积和 LAD 后蛋白质羰基化，即氧化损伤的指标。渥曼青霉素的给药降低了 Akt 的磷酸化水平，并使梗塞面积恶化。
我们得出结论，PI3K / Akt 途径对于 IH 诱导的心脏保护至关重要，并且可能是减少心肌 I / R 损伤的可行靶点。
