Sadia Khan, Ashraf Mohammad Zahid, Mishra Aastha
Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.
Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India.
Front Physiol. 2021 Nov 5;12:733453. doi: 10.3389/fphys.2021.733453. eCollection 2021.
Thrombosis remains one of the leading causes of morbidity and mortality across the world. Many pathological milieus in the body resulting from multiple risk factors escort thrombosis. Hypoxic condition is one such risk factor that disturbs the integrity of endothelial cells to cause an imbalance between anticoagulant and procoagulant proteins. Hypoxia generates reactive oxygen species (ROS) and triggers inflammatory pathways to augment the coagulation cascade. Hypoxia in cells also activates unfolded protein response (UPR) signaling pathways in the endoplasmic reticulum (ER), which tries to restore ER homeostasis and function. But the sustained UPR linked with inflammation, generation of ROS and apoptosis stimulates the severity of thrombosis in the body. Sirtuins, a group of seven proteins, play a vast role in bringing down inflammation, oxidative and ER stress and apoptosis. As a result, sirtuins might provide a therapeutic approach towards the treatment or prevention of hypoxia-induced thrombosis. Sirtuins modulate hypoxia-inducible factors (HIFs) and counteract ER stress-induced apoptosis by attenuating protein kinase RNA-like endoplasmic reticulum kinase (PERK)/Eukaryotic translation initiation factor 2α (eIF2α) pathway activation. It prevents ER-stress mediated inflammation by targeting X-Box Binding Protein 1 (XBP1) and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling through deacetylation. Sirtuins also obstruct nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome activation to reduce the expression of several pro-inflammatory molecules. It protects cells against oxidative stress by targeting nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), forkhead box O3 (FOXO3), superoxide dismutase (SOD), catalase (CAT), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), glucose-6-phosphate dehydrogenase (G6PD), phosphoglucomutase-2 (PGAM2), and NF-κB, to name few. This review, thus, discusses the potential role of sirtuins as a new treatment for hypoxia-induced thrombosis that involves an intersection of UPR and inflammatory pathways in its pathological manifestation.
血栓形成仍然是全球发病和死亡的主要原因之一。多种风险因素导致的体内许多病理环境会引发血栓形成。缺氧状态就是这样一种风险因素,它会破坏内皮细胞的完整性,导致抗凝蛋白和促凝蛋白之间的失衡。缺氧会产生活性氧(ROS)并触发炎症途径,从而增强凝血级联反应。细胞内的缺氧还会激活内质网(ER)中的未折叠蛋白反应(UPR)信号通路,该通路试图恢复内质网的稳态和功能。但是,与炎症、ROS生成和细胞凋亡相关的持续UPR会加剧体内血栓形成的严重程度。沉默调节蛋白是一组七种蛋白质,在减轻炎症、氧化应激、内质网应激和细胞凋亡方面发挥着重要作用。因此,沉默调节蛋白可能为治疗或预防缺氧诱导的血栓形成提供一种治疗方法。沉默调节蛋白调节缺氧诱导因子(HIFs),并通过减弱蛋白激酶RNA样内质网激酶(PERK)/真核翻译起始因子2α(eIF2α)途径的激活来对抗内质网应激诱导的细胞凋亡。它通过靶向X盒结合蛋白1(XBP1)并通过去乙酰化抑制活化B细胞的核因子κ轻链增强子(NF-κβ)信号传导,来预防内质网应激介导的炎症。沉默调节蛋白还会阻碍核苷酸结合结构域、富含亮氨酸的家族、含吡啉结构域3(NLRP3)炎性小体的激活,以减少几种促炎分子的表达。它通过靶向核因子红细胞2相关因子2(Nrf2)、谷胱甘肽(GSH)、叉头框O3(FOXO3)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、过氧化物酶体增殖物激活受体γ共激活因子1-α(PGC-1α)、葡萄糖-6-磷酸脱氢酶(G6PD)、磷酸葡萄糖变位酶-2(PGAM2)和NF-κB等,来保护细胞免受氧化应激。因此,本综述讨论了沉默调节蛋白作为一种新的治疗方法,用于治疗缺氧诱导的血栓形成的潜在作用,这种血栓形成在其病理表现中涉及UPR和炎症途径的交叉。