Unfolded Protein Response Differentially Modulates the Platelet Phenotype.
Unfolded Protein Response Differentially Modulates the Platelet Phenotype.
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DOI：
10.1161/circresaha.121.320530
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发表时间：
2022-08-05
影响因子：
20.1
通讯作者：
Hwa, John
中科院分区：
文献类型：
--
作者：
Jain, Kanika;Tyagi, Tarun;Du, Jing;Hu, Xiaoyue;Patell, Kanchi;Martin, Kathleen A.;Hwa, John
关键词：
未折叠蛋白反应（UPR）是一个多方面的信号级联反应，它导致蛋白质的错误折叠。虽然在有核细胞中研究得很好，但在缺乏转录调控的情况下UPR尚未被描述。血小板与心血管疾病密切相关，尽管是无核的，但对血液中的应激源反应迅速。我们研究了无核血小板中的UPR，并探讨其对血小板生理和功能的作用。使用离体和体内实验的组合研究人和小鼠血小板。血小板谱系特异性敲除小鼠是针对三种UPR途径中的每一种独立产生的，所述三种UPR途径是蛋白激酶RNA（PKR）样ER激酶（PERK）、X结合蛋白（XBP 1）和活化转录因子6（ATF 6）。前瞻性招募糖尿病（DM）患者，评价血小板在慢性病理生理疾病条件下的UPR活化。衣霉素诱导人和小鼠血小板中的IRE 1 α-XBP 1通路，而氧化应激主要激活PERK通路。PERK基因缺失可显著增加血小板聚集和凋亡，以及PLCγ2、PLCβ3和p38 MAPK的磷酸化。XBP 1缺乏可增加血小板聚集，PLCβ3和PKCδ活性增高。ATF 6缺失对血小板表型的影响相对温和，PKA增加。糖尿病患者的血小板活化与疾病严重程度、血小板活化和蛋白聚集呈正相关，仅IRE 1 α-XBP 1活化。此外，IRE 1 α抑制增加血小板聚集，而临床批准的化学伴侣4-PBA降低血小板过度活化。我们第一次表明，UPR激活发生在血小板中，可以独立于基因组调控，选择性诱导是特定的压力的来源和严重程度。每一条UPR通路都起着关键作用，并且可以不同地调节血小板活化通路和表型。靶向UPR的特定臂可能提供一种新的抗血小板策略，以减轻DM和其他心血管疾病的血栓形成风险。
Unfolded protein response (UPR) is a multifaceted signaling cascade that alleviates protein misfolding. Although well studied in nucleated cells, UPR in absence of transcriptional regulation has not been described. Intricately associated with cardiovascular diseases, platelets, despite being anucleate, respond rapidly to stressors in blood. We investigate the UPR in anucleate platelets and explore its role, if any, on platelet physiology and function. Human and mouse platelets were studied using a combination of ex vivo and in vivo experiments. Platelet lineage specific knockout mice were generated independently for each of the three UPR pathways, protein kinase RNA (PKR)-like ER kinase (PERK), X-binding protein (XBP1) and activating transcription factor 6 (ATF6). Diabetes mellitus (DM) patients were prospectively recruited and platelets were evaluated for activation of UPR under chronic pathophysiological disease conditions. Tunicamycin induced the IRE1α-XBP1 pathway in human and mouse platelets, while oxidative stress predominantly activated the PERK pathway. PERK deletion significantly increased platelet aggregation and apoptosis, and phosphorylation of PLCγ2, PLCβ3, and p38 MAPK. Deficiency of XBP1 increased platelet aggregation, with higher PLCβ3 and PKCδ activation. ATF6 deletion mediated a relatively modest effect on platelet phenotype with increased PKA. Platelets from DM patients exhibited a positive correlation between disease severity, platelet activation and protein aggregation, with only IRE1α-XBP1 activation. Moreover, IRE1α inhibition increased platelet aggregation, while clinically approved chemical chaperone, 4-PBA reduced the platelet hyperactivation. We show for the first time, that UPR activation occurs in platelets and can be independent of genomic regulation, with selective induction being specific to the source and severity of stress. Each UPR pathway plays a key role and can differentially modulate the platelet activation pathways and phenotype. Targeting the specific arms of UPR may provide a new anti-platelet strategy to mitigate thrombotic risk in DM and other cardiovascular diseases.