Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt.
Life Sci. 2020 Jul 1;252:117654. doi: 10.1016/j.lfs.2020.117654. Epub 2020 Apr 8.
Septic encephalopathy, the most frequent complication of sepsis, is orchestrated by a complex interplay of signals that leads to high mortality rates among intensive care unit patients. However, the role of the vascular endothelial growth factor receptor-2 (VEGFR2) in endoplasmic reticulum stress response (ERSR), during septic encephalopathy, is still elusive.
This study was aimed to examine the effect of an in-house designed/synthesized VEGFR2 antagonist, named WAG4S, on septic encephalopathy using cecal ligation and perforation (CLP).
Rats were intraperitoneally injected with WAG-4S (1 mg/kg/d) for 7 days post-CLP.
In septic animals, VEGFR2 antagonism declined the expression of cortical p-VEGFR2 and p-mammalian target of rapamycin complex-1 (p-mTORC1). It also worsened the behavioral and histopathological alterations beyond CLP. However, and contrary to CLP, WAG-4S decreased the p-protein kinase R-like ER kinase (p-PERK) and eukaryotic initiation factor-2α (p-eIF2α) expression. Moreover, VEGFR2 blockade upregulated the mRNA expression of activating transcription factor-4 (ATF4), binding immunoglobulin protein/glucose-regulated protein-78 (Bip/GRP78), growth arrest and DNA damage-34 (GADD34) and spliced X-box binding protein-1 (XBP1s) above CLP. Similarly, it boosted inositol requiring enzyme-1α (IRE1α) activation and redox imbalance. In the same context, WAG-4S augmented the protein levels of CLP-induced ERSR apoptotic markers, namely C/EBP homologous protein (CHOP/GADD153), c-jun N-terminal kinase (JNK) and caspase-3.
In conclusion, the PERK/eIF2α axis inhibition, during septic encephalopathy, is VEGFR2-independent, whereas the activated IRE1α/XBP1s/CHOP/JNK/caspase-3 cue promotes the ERSR execution module through VEGFR2 inhibition. This has turned VEGFR2 into a potential therapeutic target for ameliorating such an ailment.
脓毒症性脑病是脓毒症最常见的并发症，它是由一系列复杂的信号相互作用引起的，这导致重症监护病房患者的死亡率居高不下。然而，血管内皮生长因子受体-2（VEGFR2）在脓毒症性脑病中的内质网应激反应（ERSR）中的作用仍不清楚。
本研究旨在使用盲肠结扎穿孔（CLP）法，研究一种内部设计/合成的 VEGFR2 拮抗剂 WAG4S 对脓毒性脑病的影响。
CLP 后第 7 天，大鼠腹腔内注射 WAG-4S（1mg/kg/d）。
在脓毒症动物中，VEGFR2 拮抗作用降低了皮质 p-VEGFR2 和 p-雷帕霉素靶蛋白复合物-1（p-mTORC1）的表达。它还加重了 CLP 以外的行为和组织病理学改变。然而，与 CLP 相反，WAG-4S 降低了蛋白激酶 R 样内质网激酶（p-PERK）和真核起始因子-2α（p-eIF2α）的表达。此外，VEGFR2 阻断上调了激活转录因子-4（ATF4）、结合免疫球蛋白蛋白/葡萄糖调节蛋白-78（Bip/GRP78）、生长停滞和 DNA 损伤-34（GADD34）和剪接 X 盒结合蛋白-1（XBP1s）的 mRNA 表达。同样，它促进了肌醇需要酶-1α（IRE1α）的激活和氧化还原失衡。在同样的情况下，WAG-4S 增加了 CLP 诱导的 ERSR 凋亡标志物的蛋白水平，即 C/EBP 同源蛋白（CHOP/GADD153）、c-jun N 末端激酶（JNK）和半胱天冬酶-3。
总之，脓毒症性脑病中 PERK/eIF2α 轴的抑制是 VEGFR2 非依赖性的，而激活的 IRE1α/XBP1s/CHOP/JNK/caspase-3 线索通过 VEGFR2 抑制促进了 ERSR 执行模块。这使得 VEGFR2 成为改善这种疾病的潜在治疗靶点。
