AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension
AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension
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DOI：
10.1152/ajplung.00200.2012
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发表时间：
2013-01-01
影响因子：
4.9
通讯作者：
Konduri, Girija G.
中科院分区：
文献类型：
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作者：
Teng, Ru-Jeng;Du, Jianhai;Konduri, Girija G.
Teng R-J，Du J，Afolayan AJ，Eis A，Shi Y，Konduri GG。 AMP 激酶激活可改善宫内肺动脉高压肺动脉内皮细胞的血管生成。 Am J Physiol Lung Cell Mol Physiol 304：L29-L42，2013。首次发表于 2012 年 9 月 7 日； doi:10.1152/ajplung.00200.2012.-从患有宫内肺动脉高压 (IPH) 的胎儿羔羊中分离出的肺动脉内皮细胞 (PAEC) 具有表型变化，导致活性氧 (ROS) 形成增加和血管生成受损。 AMP 激活蛋白激酶 (AMPK) 已知可被 ROS 激活，预计这有助于 IPH-PAEC 的血管生成。本研究的目的是调查 IPH 中的 AMPK 反应及其在血管生成中的作用。我们观察到，与对照 PAEC 相比，IPH-PAEC 降低了 AMPK α 催化亚基和 AMPK 下游酶的磷酸化，表明 AMPK 活性降低。此外，IPH-PAEC 中 AMPK 激酶的表达减少，蛋白磷酸酶 2 增加，可能导致 AMPK 激活减少。二甲双胍是一种 AMPK 激活剂，可改善 IPH-PAEC 血管生成，同时增加内皮 NO 合酶 (eNOS) 丝氨酸 (1179) 磷酸化并减少 eNOS-caveolin-1 关联。二甲双胍还增加 MnSOD 活性以及 eNOS 和 MnSOD 的表达。二甲双胍对血管生成的增加可通过 AMPK 抑制剂化合物 C 的预处理而消除。与对照 PAEC 相比，IPH-PAEC 中血管内皮生长因子 (VEGF) 和血小板衍生生长因子 β (PDGF β) 的表达降低，并且二甲双胍未改变。这些数据表明二甲双胍通过独立于这些血管生成因子的机制改善血管生成。总之，AMPK 的激活可恢复血管生成并增加 IPH 中一氧化氮的生物利用度。二甲双胍是否有益于治疗肺动脉高压需要进一步研究。
Teng R-J, Du J, Afolayan AJ, Eis A, Shi Y, Konduri GG. AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 304: L29-L42, 2013. First published September 7, 2012; doi:10.1152/ajplung.00200.2012.-Pulmonary artery endothelial cells (PAEC) isolated from fetal lambs with in utero pulmonary hypertension (IPH) have phenotypical changes that lead to increased reactive oxygen species (ROS) formation and impaired angiogenesis. AMP-activated protein kinase (AMPK) is known to be activated by ROS, which is expected to help angiogenesis in IPH-PAEC. The objectives of this study were to investigate AMPK responses in IPH and its role in angiogenesis. We observed that, compared with control PAEC, IPH-PAEC have decreased phosphorylation of AMPK alpha catalytic subunit and AMPK downstream enzymes, indicating a decrease in AMPK activity. In addition, the expression of AMPK kinases is decreased, and protein phosphatase 2 is increased in IPH-PAEC, potentially contributing to the decreased AMPK activation. Metformin, an AMPK activator, improved IPH-PAEC angiogenesis while increasing endothelial NO synthase (eNOS) serine(1179) phosphorylation and decreasing the eNOS-caveolin-1 association. Metformin also increased MnSOD activity and the expression of both eNOS and MnSOD. The increase in angiogenesis by Metformin is abolished by pretreatment with AMPK inhibitor, Compound C. Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor beta (PDGF beta) are decreased in IPH-PAEC compared with control PAEC and were not altered by Metformin. These data indicate that Metformin improves angiogenesis through mechanisms independent of these angiogenic factors. In conclusion, activation of AMPK restores angiogenesis and increases the bioavailability of nitric oxide in IPH. Whether Metformin is beneficial in the management of pulmonary hypertension requires further investigation.