Erythrocyte mitogen-activated protein kinases mediate hemolytic events under osmotic and oxidative stress and in hemolytic diseases.
Erythrocyte mitogen-activated protein kinases mediate hemolytic events under osmotic and oxidative stress and in hemolytic diseases.
复制标题
DOI：
10.1016/j.cellsig.2022.110450
复制
发表时间：
2022-11
影响因子：
4.8
通讯作者：
Kanias, Tamir
中科院分区：
文献类型：
--
作者：
Hazegh, Kelsey;Fang, Fang;Kelly, Kathleen;Sinchar, Derek;Wang, Ling;Zuchelkowski, Benjamin E;Ufelle, Alexander C;Esparza, Orlando;Davizon-Castillo, Pavel;Page, Grier P;Kanias, Tamir
p38 MAPK是细胞适应各种应激刺激的关键调节因子，然而，它们在介导红细胞死亡和溶血中的作用在很大程度上是未知的。我们假设红细胞p38 MAPK的激活是刺激溶血的常见事件，并且抑制p38 MAPK通路可以减轻血红蛋白病中的溶血。我们将人红细胞暴露于二酰胺诱导的氧化应激或在存在或不存在p38 MAPK抑制剂（SCIO 469，SB 203580，CMPD 1）的情况下低渗休克，并使用免疫印迹法测定MAPK活性，并确定可能的p38 MAPK下游效应子。我们还评估了p38 MAPK抑制剂对镰状细胞病小鼠模型红细胞中应激诱导的溶血或缺氧诱导的镰状化的影响。我们发现，人类红细胞表达常规MAPK（MKK 3，p38 MAPK，MAPKAPK 2），并确定了不同的MAPK激活途径在每种应激条件下。具体而言，在二酰胺处理的红细胞中p38 MAPK抑制与Src酪氨酸激酶和带3蛋白磷酸化降低相关。相反，低渗休克诱导MAPKAPK 2和RSK 2磷酸化，SCIO 469或CMPD 1抑制。与血红蛋白病相关，与健康个体的红细胞相比，镰状细胞病与红细胞MKK3、p38 MAPK和MAPKAPK2表达和磷酸化增加相关。此外，p38 MAPK抑制与减少溶血反应二酰胺治疗或渗透压休克，并减少红细胞镰状化实验缺氧。这些发现提供了对MAPK介导的信号通路的见解，该信号通路调节红细胞功能和溶血以响应细胞外应激物或人类疾病。
p38 MAPKs are key regulators of cellular adaptation to various stress stimuli, however, their role in mediating erythrocyte cell death and hemolysis is largely unknown. We hypothesized that activation of erythrocyte p38 MAPK is a common event in the stimulation of hemolysis, and that inhibition of p38 MAPK pathways could mitigate hemolysis in hemoglobinopathies. We exposed human erythrocytes to diamide-induced oxidative stress or to hypoosmotic shock in the presence or absence of p38 MAPK inhibitors (SCIO469, SB203580, CMPD1) and used immunoblotting to determine MAPK activity and to identify possible downstream effectors of p38 MAPK. We also evaluated the impact of p38 MAPK inhibitors on stress-induced hemolysis or hypoxia-induced sickling in erythrocytes from mouse models of sickle cell disease. We found that human erythrocytes express conventional MAPKs (MKK3, p38 MAPK, MAPKAPK2) and identified differential MAPK activation pathways in each stress condition. Specifically, p38 MAPK inhibition in diamide-treated erythrocytes was associated with decreased phosphorylation of Src tyrosine kinases and Band 3 protein. Conversely, hypoosmotic shock induced MAPKAPK2 and RSK2 phosphorylation, which was inhibited by SCIO469 or CMPD1. Relevant to hemoglobinopathies, sickle cell disease was associated with increased erythrocyte MKK3, p38 MAPK, and MAPKAPK2 expression and phosphorylation as compared with erythrocytes from healthy individuals. Furthermore, p38 MAPK inhibition was associated with decreased hemolysis in response to diamide treatments or osmotic shock, and with decreased erythrocyte sickling under experimental hypoxia. These findings provided insights into MAPK-mediated signaling pathways that regulate erythrocyte function and hemolysis in response to extracellular stressors or human diseases.