Chong Zhao Zhong, Shang Yan Chen, Maiese Kenneth
Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Curr Neurovasc Res. 2007 Aug;4(3):194-204. doi: 10.2174/156720207781387150.
Impacting a significant portion of the world's population with increasing incidence in minorities, the young, and the physically active, diabetes mellitus (DM) and its complications affect approximately 20 million individuals in the United States and over 100 million individuals worldwide. In particular, vascular disease from DM may lead to some of the most serious complications that can extend into both the cardiac and nervous systems. Unique strategies that can prevent endothelial cell (EC) demise and elucidate novel cellular mechanisms for vascular cytoprotection become vital for the prevention and treatment of vascular DM complications. Here, we demonstrate that erythropoietin (EPO), an agent that has recently been shown to extend cell viability in a number of systems extending beyond hematopoietic cells, prevents EC injury and apoptotic nuclear DNA degradation during elevated glucose exposure. More importantly, EPO employs Wnt1, a cysteine-rich glycosylated protein involved in gene expression, cell differentiation, and cell apoptosis, to confer EC cytoprotection and maintains the integrity of Wnt1 expression during elevated glucose exposure. In addition, application of anti-Wnt1 neutralizing antibody abrogates the protective capacity of both EPO and Wnt1, illustrating that Wnt1 is an important component in the cytoprotection of ECs during elevated glucose exposure. Intimately linked to this cytoprotection is the downstream Wnt1 pathway of glycogen synthase kinase (GSK-3beta) that requires phosphorylation of GSK-3beta and inhibition of its activity by EPO. Interestingly, inhibition of GSK-3beta activity during elevated glucose leads to enhanced EC survival, but does not synergistically improve protection by EPO or Wnt1, suggesting that EPO and Wnt1 are closely tied to the blockade of GSK-3beta activity. Our work exemplifies an exciting potential application for EPO in regards to the treatment of DM vascular disease complications and highlights a previously unrecognized role for Wnt1 and the modulation of the downstream pathway of GSK-3beta to promote vascular cell viability during DM.
糖尿病（DM）及其并发症影响着世界上很大一部分人口，在少数族裔、年轻人和体育活动人群中的发病率不断上升，在美国约有2000万人受其影响，全球超过1亿人。特别是，糖尿病引起的血管疾病可能导致一些最严重的并发症，这些并发症可累及心脏和神经系统。能够防止内皮细胞（EC）死亡并阐明血管细胞保护新细胞机制的独特策略，对于预防和治疗糖尿病血管并发症至关重要。在此，我们证明促红细胞生成素（EPO），一种最近已被证明在许多系统中（不仅仅是造血细胞）可延长细胞活力的物质，能预防高糖暴露期间的内皮细胞损伤和凋亡性核DNA降解。更重要的是，EPO利用Wnt1（一种参与基因表达、细胞分化和细胞凋亡的富含半胱氨酸的糖蛋白）赋予内皮细胞细胞保护作用，并在高糖暴露期间维持Wnt1表达的完整性。此外，应用抗Wnt1中和抗体可消除EPO和Wnt1的保护能力，表明Wnt1是高糖暴露期间内皮细胞细胞保护的重要组成部分。与这种细胞保护密切相关的是糖原合酶激酶（GSK - 3β）的下游Wnt1途径，该途径需要GSK - 3β的磷酸化并被EPO抑制其活性。有趣的是，高糖期间抑制GSK - 3β活性可提高内皮细胞存活率，但不能协同增强EPO或Wnt1的保护作用，这表明EPO和Wnt1与GSK - 3β活性的阻断密切相关。我们的工作例证了EPO在治疗糖尿病血管疾病并发症方面令人兴奋的潜在应用，并突出了Wnt1以及GSK - 3β下游途径的调节在糖尿病期间促进血管细胞活力方面以前未被认识的作用。
