PP2A contributes to endothelial death in high glucose: inhibition by benfotiamine
PP2A contributes to endothelial death in high glucose: inhibition by benfotiamine
复制标题
DOI：
10.1152/ajpregu.00676.2009
复制
发表时间：
2010-12-01
影响因子：
2.8
通讯作者：
Kern, T. S.
中科院分区：
文献类型：
--
作者：
Du, Y.;Kowluru, A.;Kern, T. S.
杜 Y，Kowluru A，克恩 TS。 PP2A 在高葡萄糖条件下导致内皮细胞死亡：苯磷硫胺的抑制作用。 Am J Physiol Regul Integr Comp Physiol 299：R1610-R1617，2010。首次发表于 2010 年 9 月 29 日； doi:10.1152/ajpregu.00676.2009.-内皮细胞死亡在糖尿病血管疾病中至关重要，但调节因素仅得到部分阐明。磷酸酶在细胞代谢中发挥重要的调节作用，但此前并未涉及高血糖诱导的细胞死亡。我们研究了磷酸酶、2A 型蛋白磷酸酶 (PP2A) 在高血糖诱导的牛主动脉内皮细胞 (BAEC) 信号传导变化和死亡中的作用。我们还探讨了苯磷硫胺对这种磷酸酶的影响。通过甲基化程度和活性测量来评估 BAEC 中 PP2A 的激活，并使用选择性药理学（冈田酸、磷霉素钠）和分子（小干扰 RNA）方法抑制该酶。在 30 mM 葡萄糖中培养的 BAEC 显着增加了 PP2A 甲基化和活性，而 PP2A 抑制剂可阻止这些异常。糖尿病大鼠的主动脉和视网膜中的 PP2A 活性也有所增加。 BAEC 中的 NF-kappa B 活性和细胞死亡在 30 mM 葡萄糖中显着增加，并被 PP2A 抑制所抑制。 NF-kappa B 在高血糖诱导的 BAEC 死亡中发挥了作用，因为用 SN50 阻断其易位也能抑制细胞死亡。抑制 PP2A 可阻断高血糖诱导的 NF-κ B 和 Bad 去磷酸化，从而有利于细胞存活。苯磷硫胺与 BAEC 一起孵育可抑制高葡萄糖诱导的 PP2A 和 NF-κ B 激活和细胞死亡，以及其他几种代谢缺陷，这些缺陷同样受到 PP2A 抑制剂的抑制。 PP2A 的激活导致高葡萄糖条件下的内皮细胞死亡，苯磷硫胺的有益作用至少部分归因于抑制 PP2A 激活。
Du Y, Kowluru A, Kern TS. PP2A contributes to endothelial death in high glucose: inhibition by benfotiamine. Am J Physiol Regul Integr Comp Physiol 299: R1610-R1617, 2010. First published September 29, 2010; doi:10.1152/ajpregu.00676.2009.-Endothelial death is critical in diabetic vascular diseases, but regulating factors have been only partially elucidated. Phosphatases play important regulatory roles in cell metabolism, but have not previously been implicated in hyperglycemia-induced cell death. We investigated the role of the phosphatase, type 2A protein phosphatase (PP2A), in hyperglycemia-induced changes in signaling and death in bovine aortic endothelial cells (BAEC). We explored also the influence of benfotiamine on this phosphatase. Activation of PP2A was assessed in BAEC by the extent of methylation and measurement of activity, and the enzyme was inhibited using selective pharmacological (okadaic acid, sodium fostriecin) and molecular (small interfering RNA) approaches. BAECs cultured in 30 mM glucose significantly increased PP2A methylation and activity, and PP2A inhibitors blocked these abnormalities. PP2A activity was increased also in aorta and retina from diabetic rats. NF-kappa B activity and cell death in BAEC were significantly increased in 30 mM glucose and inhibited by PP2A inhibition. NF-kappa B played a role in the hyperglycemia-induced death of BAEC, since blocking its translocation with SN50 also inhibited cell death. Inhibition of PP2A blocked the hyperglycemia-induced dephosphorylation of NF-kappa B and Bad, thus favoring cell survival. Incubation of benfotiamine with BAEC inhibited the high glucose-induced activation of PP2A and NF-kappa B and cell death, as well as several other metabolic defects, which likewise were inhibited by inhibitors of PP2A. Activation of PP2A contributes to endothelial cell death in high glucose, and beneficial actions of benfotiamine are due, at least in part, to inhibition of PP2A activation.