Department of Pharmacology, Geriatric Research Education and Clinical Center, VA Medical Center, University of Minnesota, Minneapolis, MN, USA.
Mol Neurobiol. 2010 Jun;41(2-3):384-91. doi: 10.1007/s12035-010-8122-8. Epub 2010 Apr 6.
The use of statins for the prevention or treatment of different neurodegenerative diseases has generated considerable interest albeit with some controversy. Mechanisms of statin-induced neuroprotection are not well understood. Recently, we reported that simvastatin stimulated neuronal gene expression and protein levels of the major antiapoptotic protein Bcl-2 in vivo and in vitro; suppression of Bcl-2 in SH-SY5Y cells reduced simvastatin neuroprotection; effects were independent of cholesterol and other products of the 3-hydroxy-3-methylglutaryl-CoA reductase pathway. Endothelin-1 (ET-1) can increase Bcl-2 abundance via the transcription factor nuclear factor of activated thymocytes (NFATc), and simvastatin was reported to increase ET-1 gene expression. We tested the hypothesis that simvastatin stimulation of Bcl-2 involves up-regulation of ET-1 and binding of NFATc to Bcl-2 promoter sites in SH-SY5Y human neuroblastoma cells. Simvastatin increased both intracellular and secreted ET-1 protein levels. Exogenous ET-1 increased Bcl-2 protein abundance, which was inhibited by ET-1 receptor antagonists. Simvastatin increased translocation of NFATc3 to the nucleus while reducing nuclear NFATc1 and having no effect on NFATc4. Endothelin-1 also increased NFATc3 levels in the nucleus, and this increase was inhibited by ET-1 receptor antagonists. Treatment of cells with simvastatin stimulated binding of NFATc3 to the Bcl-2 promoter. We report novel findings showing that up-regulation of Bcl-2 by simvastatin involves ET-1 and the transcription factor NFATc3. Discovering how statins can selectively alter a specific NFATc isoform that leads to an increase in an antiapoptotic protein will provide a new approach to understanding statin-induced neuroprotection and conditions outside the brain in which apoptosis contributes to pathophysiology.
他汀类药物用于预防或治疗不同神经退行性疾病引起了相当大的兴趣，尽管存在一些争议。他汀类药物诱导神经保护的机制尚不清楚。最近，我们报道辛伐他汀在体内和体外刺激神经元基因表达和主要抗凋亡蛋白 Bcl-2 的蛋白水平；SH-SY5Y 细胞中 Bcl-2 的抑制减少了辛伐他汀的神经保护作用；这些作用与胆固醇和 3-羟-3-甲基戊二酰辅酶 A 还原酶途径的其他产物无关。内皮素-1（ET-1）可以通过激活的胸腺细胞核因子（NFATc）增加 Bcl-2 的丰度，并且据报道辛伐他汀增加 ET-1 基因表达。我们检验了这样一个假设，即辛伐他汀对 Bcl-2 的刺激涉及 ET-1 的上调和 NFATc 结合到 SH-SY5Y 人神经母细胞瘤细胞的 Bcl-2 启动子位点。辛伐他汀增加了细胞内和分泌的 ET-1 蛋白水平。外源性 ET-1 增加了 Bcl-2 蛋白的丰度，而 ET-1 受体拮抗剂则抑制了这一作用。辛伐他汀增加 NFATc3 向核内易位，同时减少核内 NFATc1 而对 NFATc4 没有影响。内皮素-1 也增加了核内 NFATc3 的水平，而这种增加被内皮素-1 受体拮抗剂抑制。用辛伐他汀处理细胞刺激 NFATc3 与 Bcl-2 启动子结合。我们报告了新的发现，表明辛伐他汀上调 Bcl-2 涉及 ET-1 和转录因子 NFATc3。发现他汀类药物如何能选择性地改变特定的 NFATc 同工型，导致抗凋亡蛋白的增加，将为理解他汀类药物诱导的神经保护以及大脑以外导致病理生理学的细胞凋亡的情况提供一种新的方法。
