Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes.
Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes.
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DOI：
10.1038/s41419-018-0501-5
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Zhang SX
中科院分区：
文献类型：
--
作者：
Bhatta M;Chatpar K;Hu Z;Wang JJ;Zhang SX
糖尿病中持续的血管损伤和变性部分归因于血管生成细胞的修复功能缺陷。我们最近的工作表明内质网（ER）应激与高葡萄糖诱导的骨髓（BM）祖细胞功能障碍有关。在此，我们研究了内质网应激在链脲佐菌素诱导的糖尿病小鼠血管生成异常中的体内作用。我们的数据表明，BM 单核细胞和造血祖细胞中的 ER 应激标志物和炎症基因表达随着疾病进展而动态增加。糖尿病 3 个月后，在骨髓来源的早期生长细胞 (EOC) 中观察到 CHOP 和裂解的 caspase 3 水平增加。通过离体或体内化学伴侣治疗抑制 ER 应激，可显着改善糖尿病 EOC 的生成和迁移，同时减少这些细胞的凋亡。化学伴侣治疗还增加了糖尿病小鼠的外周血中循环血管生成细胞的数量，减轻了BM病理学，并增强了缺血/再灌注后的视网膜血管修复。从机制上讲，CHOP 的敲低可减轻高葡萄糖诱导的 EOC 功能障碍并减轻细胞凋亡，表明 CHOP 在介导糖尿病中内质网应激相关的血管生成细胞损伤中发挥着关键作用。总之，我们的研究表明，靶向 ER 信号传导可能为增强糖尿病的血管生成功能提供一种有前景的新颖方法。
Persistent vascular injury and degeneration in diabetes are attributed in part to defective reparatory function of angiogenic cells. Our recent work implicates endoplasmic reticulum (ER) stress in high-glucose-induced bone marrow (BM) progenitor dysfunction. Herein, we investigated the in vivo role of ER stress in angiogenic abnormalities of streptozotocin-induced diabetic mice. Our data demonstrate that ER stress markers and inflammatory gene expression in BM mononuclear cells and hematopoietic progenitor cells increase dynamically with disease progression. Increased CHOP and cleaved caspase 3 levels were observed in BM-derived early outgrowth cells (EOCs) after 3 months of diabetes. Inhibition of ER stress by ex vivo or in vivo chemical chaperone treatment significantly improved the generation and migration of diabetic EOCs while reducing apoptosis of these cells. Chemical chaperone treatment also increased the number of circulating angiogenic cells in peripheral blood, alleviated BM pathology, and enhanced retinal vascular repair following ischemia/reperfusion in diabetic mice. Mechanistically, knockdown of CHOP alleviated high-glucose-induced EOC dysfunction and mitigated apoptosis, suggesting a pivotal role of CHOP in mediating ER stress-associated angiogenic cell injury in diabetes. Together, our study suggests that targeting ER signaling may provide a promising and novel approach to enhancing angiogenic function in diabetes.
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影响因子：
--
作者：
Lenna, Stefania;Farina, Alessandra G.;Martyanov, Viktor;Christmann, Romy B.;Wood, Tammara A.;Farber, Harrison W.;Scorza, Raffaella;Whitfield, Michael L.;Lafyatis, Robert;Trojanowska, Maria
通讯作者：
Trojanowska, Maria
影响因子：
15.9
作者：
Mizutani, M;Kern, TS;Lorenzi, M
通讯作者：
Lorenzi, M
影响因子：
7.7
作者：
Caballero, Sergio;Sengupta, Nilanjana;Grant, Maria B.
通讯作者：
Grant, Maria B.
影响因子：
5.2
作者：
Challen, GA;Little, MH
通讯作者：
Little, MH
内质网应激与视网膜炎症和糖尿病性视网膜病有关。
影响因子：
3.5
作者：
Li, Jingming;Wang, Joshua J.;Yu, Qiang;Wang, Min;Zhang, Sarah X.
通讯作者：
Zhang, Sarah X.