Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation.
Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation.
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DOI：
10.2174/156720210791184899
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发表时间：
2010-05
影响因子：
2.1
通讯作者：
Maiese K
中科院分区：
文献类型：
--
作者：
Hou J;Chong ZZ;Shang YC;Maiese K
糖尿病（DM）的并发症严重影响内皮细胞，最终影响多个器官系统。这些问题需要创新的治疗策略，采用负责细胞存活和寿命的分子途径。在这里，我们表明，在临床相关的糖尿病模型与升高的D-葡萄糖，内皮细胞（EC）SIRT 1是至关重要的预防早期膜凋亡磷脂酰丝氨酸外化和随后的DNA降解与SIRT 1活性的调节和基因敲低SIRT 1的研究支持。此外，在升高的D-葡萄糖暴露期间，我们表明SIRT 1被隔离在EC的细胞质中，但是SIRT 1的特异性激活将蛋白质运送到细胞核以允许细胞保护。SIRT 1避免细胞凋亡的能力利用蛋白激酶B（Akt 1）的激活、叉头成员FoxO 3a的翻译后磷酸化、FoxO 3a向细胞核的运输的阻断以及FoxO 3a的抑制来启动“促细胞凋亡”程序，如FoxO 3a的互补基因敲低研究所示。SIRT 1的血管凋亡监督延伸到线粒体膜通透性、细胞色素c释放、Bad活化以及半胱天冬酶1和3活化的直接调节，因为SIRT 1活性的抑制和SIRT 1的基因敲低显著加重级联进展，而SIRT 1活化废除这些凋亡元件。我们的工作确定了血管SIRT 1及其对早期凋亡膜信号传导、Akt 1激活、FoxO 3a翻译后修饰和运输、线粒体通透性、Bad激活和快速caspase诱导的控制，作为治疗DM期间血管并发症的新途径。
Complications of diabetes mellitus (DM) weigh heavily upon the endothelium that ultimately affect multiple organ systems. These concerns call for innovative treatment strategies that employ molecular pathways responsible for cell survival and longevity. Here we show in a clinically relevant model of DM with elevated D-glucose that endothelial cell (EC) SIRT1 is vital for the prevention of early membrane apoptotic phosphatidylserine externalization and subsequent DNA degradation supported by studies with modulation of SIRT1 activity and gene knockdown of SIRT1. Furthermore, during elevated D-glucose exposure, we show that SIRT1 is sequestered in the cytoplasm of ECs, but specific activation of SIRT1 shuttles the protein to the nucleus to allow for cytoprotection. The ability of SIRT1 to avert apoptosis employs the activation of protein kinase B (Akt1), the post-translational phosphorylation of the forkhead member FoxO3a, the blocked trafficking of FoxO3a to the nucleus, and the inhibition of FoxO3a to initiate a “pro-apoptotic” program as shown by complimentary gene knockdown studies of FoxO3a. Vascular apoptotic oversight by SIRT1 extends to the direct modulation of mitochondrial membrane permeability, cytochrome c release, Bad activation, and caspase 1 and 3 activation, since inhibition of SIRT1 activity and gene knockdown of SIRT1 significantly accentuate cascade progression while SIRT1 activation abrogates these apoptotic elements. Our work identifies vascular SIRT1 and its control over early apoptotic membrane signaling, Akt1 activation, post-translational modification and trafficking of FoxO3a, mitochondrial permeability, Bad activation, and rapid caspase induction as new avenues for the treatment of vascular complications during DM.
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影响因子：
2.1
作者：
Chong ZZ;Maiese K
通讯作者：
Maiese K
影响因子：
4.8
作者：
Balan, Vitaly;Miller, Gregory S.;Tzivion, Guri
通讯作者：
Tzivion, Guri
DOI：
10.1007/978-0-387-75681-3_37
发表时间：
2009-01-01
期刊：
TAURINE 7
影响因子：
--
作者：
Gossai, Davekanand;Lau-Cam, Cesar A.
通讯作者：
Lau-Cam, Cesar A.
影响因子：
7.7
作者：
Ceriello, A;delloRusso, P;Cerutti, P
通讯作者：
Cerutti, P
影响因子：
10.9
作者：
Canto, Caries;Auwerx, Johan
通讯作者：
Auwerx, Johan