Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity
Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity
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DOI：
10.1016/j.bcp.2016.12.009
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发表时间：
2017-03-01
影响因子：
5.8
通讯作者：
Agouni, Abdelali
中科院分区：
文献类型：
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作者：
Maamoun, Hatem;Zachariah, Matshediso;Agouni, Abdelali
糖尿病心血管并发症的主要原因是血管内皮功能障碍和血管生成障碍。内质网（ER）和氧化应激被证明在糖尿病内皮功能障碍的发展中发挥关键作用。血红素加氧酶-1（H 0 -1）已被证明可以保护糖尿病患者免受氧化应激的影响;然而，其在缓解ER应激诱导的内皮功能障碍中的作用尚未完全阐明。本研究旨在检测HO-1对高糖介导的内质网应激和内皮功能障碍的保护作用，并了解其在氧化应激、炎症和细胞死亡等方面的作用机制（CoPP，HO-1诱导剂）或4-苯基丁酸（PBA，ER应激抑制剂）。使用一个集成的细胞和分子的方法，我们然后评估ER应激和炎症反应，除了在这些cells.Our结果表明，HO-1诱导阻止高糖介导的关键ER应激标志物的mRNA和蛋白质表达的增加的细胞凋亡和血管生成能力。与高糖孵育的细胞表现出高水平的氧化应激，激活主要的炎症和凋亡反应[核因子（NF）-κ B和c-jun N-末端激酶（INK）]，并增加凋亡率;然而，用CoPP或PBA预处理的细胞得到充分保护。此外，高葡萄糖增强半胱天冬酶3和7的切割和活性，并增加切割的聚ADP核糖聚合酶（PARP）的表达，而HO-1诱导阻止这些影响。最后，HO-1诱导和ER应激抑制阻止了高糖诱导的NO释放减少，损害了HUVECs的血管生成能力，并增强了血管内皮生长因子（VEGF）-A的表达。我们在此显示了内质网应激介导的细胞死亡在糖尿病诱导的内皮功能障碍和血管生成受损中的关键作用，并强调了HO-1在糖尿病诱导的血管生成中的作用。1诱导作为缺血性疾病和糖尿病中ER应激反应的关键治疗调节剂。我们的研究结果还强调了ER应激反应和氧化应激之间复杂的相互作用。(C)2016 Elsevier Inc. All rights reserved.
Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes. Hemeoxygenase-1 (H0-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death.Human Umbilical Vein Endothelial Cells (HUVECs) were grown in either physiological or intermittent high concentrations of glucose for 5 days in the presence or absence of Cobalt (III) Protoporphyrin IX chloride (CoPP, HO-1 inducer) or 4-Phenyl Butyric Acid (PBA, ER stress inhibitor). Using an integrated cellular and molecular approach, we then assessed ER stress and inflammatory responses, in addition to apoptosis and angiogenic capacity in these cells.Our results show that HO-1 induction prevented high glucose-mediated increase of mRNA and protein expression of key ER stress markers. Cells incubated with high glucose exhibited high levels of oxidative stress, activation of major inflammatory and apoptotic responses [nuclear factor (NF)-kappa B and c-jun N-terminal kinase (INK)] and increased rate of apoptosis; however, cells pre-treated with CoPP or PBA were fully protected. In addition, high glucose enhanced caspases 3 and 7 cleavage and activity and augmented cleaved poly ADP ribose polymerase (PARP) expression whereas HO-1 induction prevented these effects. Finally, HO-1 induction and ER stress inhibition prevented high glucose-induced reduction in NO release and impaired the angiogenic capacity of HUVECs, and enhanced vascular endothelial growth factor (VEGF)-A expression.Altogether, we show here the critical role of ER stress-mediated cell death in diabetes-induced endothelial dysfunction and impaired angiogenesis and underscore the role of HO-1 induction as a key therapeutic modulator for ER stress response in ischemic disorders and diabetes. Our results also highlight the complex interplay between ER stress response and oxidative stress. (C) 2016 Elsevier Inc. All rights reserved.