Inhibition of phosphatidylinositol 3-kinase/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells.
Inhibition of phosphatidylinositol 3-kinase/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells.
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DOI：
10.1097/fjc.0000000000000014
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发表时间：
2013-12
影响因子：
3
通讯作者：
Klemm DJ
中科院分区：
文献类型：
--
作者：
Garat CV;Crossno JT Jr;Sullivan TM;Reusch JE;Klemm DJ
低氧诱导的肺动脉高压的特征是肺动脉（PA）系统的进行性重塑和PA平滑肌细胞（SMCs）中转录因子cAMP反应元件结合蛋白（CREB）的缺失。先前的体外研究表明，血小板衍生生长因子（一种在缺氧动脉壁中产生的丝裂原）通过PI3K/Akt通路引起内侧SMCs中CREB的丢失。这些事件触发SMCs从静止的、收缩的表型转变为增生的、迁移的、去分化的和合成的表型，这有助于PA增厚。在这里，我们研究了抑制PI3K或Akt是否可以减轻慢性缺氧大鼠肺动脉重塑并防止PA内侧SMCs的CREB丢失。抑制酶钝化缺氧诱导的PA重塑和SMC CREB消耗，减少SMC增殖和胶原沉积。抑制Akt，而非PI3K，抑制远端小动脉的肌肉化，钝化右心室肥厚。有趣的是，在未治疗组和抑制剂治疗组中，平均PA压因缺氧而升高相同，但在Rho激酶抑制剂法舒地尔（Fasudil）的作用下，PA压迅速恢复正常。我们得出结论，PI3K和Akt抑制剂可以减轻缺氧诱导的PA重塑和SMC CREB耗竭，但由于它们无法抑制Rho激酶介导的血管收缩，因此无法阻断肺动脉高压的发展。
Hypoxia-induced pulmonary hypertension is characterized by progressive remodeling of the pulmonary artery (PA) system and loss of the transcription factor, cAMP response element binding protein (CREB) in PA smooth muscle cells (SMCs). Previous in vitro studies suggested that platelet-derived growth factor, a mitogen produced in the hypoxic arterial wall, elicits loss of CREB in medial SMCs via the PI3K/Akt pathway. These events trigger switching of SMCs from a quiescent, contractile phenotype to a proliferative, migratory, dedifferentiated, and synthetic phenotype, which contributes to PA thickening. Here, we investigated whether inhibition of PI3K or Akt could attenuate arterial remodeling in the lung and prevent CREB loss in PA medial SMCs in rats subjected to chronic hypoxia. Inhibition of either enzyme-blunted hypoxia-induced PA remodeling and SMC CREB depletion and diminished SMC proliferation and collagen deposition. Inhibition of Akt, but not PI3K, suppressed muscularization of distal arterioles and blunted right ventricular hypertrophy. Interestingly, mean PA pressure was elevated equally by hypoxia in untreated and inhibitor-treated groups but was normalized acutely by the Rho kinase inhibitor, Fasudil. We conclude that PI3K and Akt inhibitors can attenuate hypoxia-induced PA remodeling and SMC CREB depletion but fail to block the development of pulmonary hypertension because of their inability to repress Rho kinase–mediated vasoconstriction.