Early expression of myocardial HIF-1α in response to mechanical stresses -: Regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway
Early expression of myocardial HIF-1α in response to mechanical stresses -: Regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway
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DOI：
10.1161/hh0202.104923
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发表时间：
2002-02-08
影响因子：
20.1
通讯作者：
Kim, MS
中科院分区：
文献类型：
--
作者：
Kim, CH;Cho, YS;Kim, MS
缺氧诱导因子-1（HIF-1）可上调缺血组织和生长肿瘤中血管内皮生长因子（VEGF）的表达。正常情况下，HIF-1活性取决于HIF-1 α亚基的数量，而HIF-1 α亚基的数量受氧张力的严格调节。在心肌中，VEGF的表达已被证明是在非缺氧条件下由机械应力诱导的。然而，应激介导的VEGF诱导的细胞机制仍不清楚。因此，我们研究了HIF-1可能参与大鼠心脏中应激介导的VEGF诱导。在这项研究中，我们使用3种不同的方法增加左心室壁张力，即通过诱导局部缺血，通过扩张心室内球囊，以及通过使用下腔静脉分流产生血流动力学过载。在所有情况下，HIF-1 α积累在心肌细胞的细胞核中的早期阶段，这是随后的VEGF诱导。磷脂酰肌醇3-激酶（PI3K）依赖性Akt磷酸化被机械应力激活，并完全阻断渥曼青霉素（PI3K抑制剂）。此外，应激介导的HIF-1 α和VEGF诱导被钆（一种牵张激活通道抑制剂）、渥曼青霉素和雷帕霉素（一种FRAP抑制剂）抑制。我们的研究结果表明，HIF-1 α在诱导VEGF在非缺血和机械应激心肌中起着重要作用，这是由牵张激活通道和PI3K/Akt/FRAP通路调节。此外，这种诱导HIF-1 α的信号通路似乎在心肌对应激的适应中起重要作用。这篇文章的全文可以在www.example.com上找到。
Vascular endothelial growth factor (VEGF) expression is upregulated by hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. Normally, HIF-1 activity depends on the amount of HIF-1alpha subunit, which is tightly regulated by the oxygen tension. In the myocardium, VEGF expression has been shown to be induced under nonhypoxic conditions by mechanical stresses. However, the cellular mechanism of stress-mediated VEGF induction remains unclear. Therefore, we examined the possible involvement of HIF-1 in stress-mediated VEGF induction in rat hearts, In this study, we increased the left ventricular wall tension using 3 different methods, namely by inducing regional ischemia, by expanding an intraventricular balloon, and by producing hemodynamic overload using an aortocaval shunt. In all cases, HIF-1alpha accumulated in the nuclei of cardiac myocytes in the early phase, and this was followed by VEGF induction. Phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation was found to be activated by mechanical stress and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the stress-mediated induction of HIF-1alpha and VEGF was suppressed by gadolinium (a stretch-activated channel inhibitor), wortmannin, and rapamycin (a FRAP inhibitor). Our results suggest that HIF-1alpha plays an important role in the induction of VEGF in nonischemic and mechanically stressed myocardium, and that this is regulated by stretch-activated channels and the PI3K/Akt/FRAP pathway. Moreover, this signaling pathway, which induces HIF-1alpha, seems to play an important role in the adaptation of the myocardium to stresses. The full text of this article is available at http://www.circresaha.org.