FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-κB-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model
FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-κB-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model
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DOI：
10.1152/ajpendo.00005.2010
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发表时间：
2010-09-01
影响因子：
5.1
通讯作者：
Du, Jie
中科院分区：
文献类型：
--
作者：
Liu, Shu;Shen, Hua;Du, Jie
Liu S，Shen H，Xu M，Liu O，Zhao L，Liu S，Guo Z，Du J. FRP inhibits ox-LDL-induced endothelial cell apoptosis through a Akt-NF-kappa B-Bcl-2 pathway and inhibits endothelial cell apoptosis in a apoE-knockout mouse model. Am J Physiol Endocrinol Metab 299：E351-E363，2010.首次发表于2010年6月8日; doi：10.1152/ajpendo.00005.2010.-动脉粥样硬化是世界上最常见的心血管疾病的原因。虽然动脉粥样硬化的发展似乎是多种适应不良途径的结果，但动脉粥样硬化发病机制中特别重要的因素是氧化低密度脂蛋白（ox-LDL），其导致内皮损伤。来自我们实验室和其他实验室的数据表明，在血管中表达的卵泡抑素相关蛋白（FRP）具有心脏保护作用，这表明FRP保护的丧失可能在动脉粥样硬化的发展中发挥作用。在本研究中，我们确定FRP过表达是否能保护内皮细胞（EC）损伤，这是动脉粥样硬化的中间终点。我们培育了FRP+转基因（过度表达FRP）的apoE基因敲除（apoE（-/-））小鼠。我们将它们与对照组小鼠（同窝出生的小鼠）进行比较。分离人脐静脉内皮细胞（HUVECs），用ox-LDL和重组FRP处理。分析FRP诱导的信号转导及Bcl-2 mRNA和蛋白的稳定性。16周后，apoE（-/-）FRP+小鼠的凋亡EC明显少于对照组。体外实验表明，FRP对EC凋亡的影响是通过上调抗凋亡蛋白Bcl-2的表达介导的。在HUVECs中，FRP通过PI 3 K-Akt-NF-κ B途径上调Bcl-2的转录。我们的结论是，FRP过表达通过Bcl-2上调阻止细胞凋亡来维持EC活力。FRP可能是预防和治疗血管EC损伤和动脉粥样硬化的新的治疗靶点。
Liu S, Shen H, Xu M, Liu O, Zhao L, Liu S, Guo Z, Du J. FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-kappa B-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model. Am J Physiol Endocrinol Metab 299: E351-E363, 2010. First published June 8, 2010; doi:10.1152/ajpendo.00005.2010.-Atherosclerosis is the most common cause of cardiovascular diseases in the world. Although the development of atherosclerosis appears to be the result of multiple maladaptive pathways, a particularly important factor in the pathogenesis of atherosclerosis is oxidized low-density lipoprotein (ox-LDL), which contributes to endothelial damage. Data from our laboratory and others show that follistatin-related protein (FRP), which is expressed in the vasculature, has cardioprotective effects, suggesting that loss of FRP protection might play a role in the development of atherosclerosis. In the present study, we determined whether FRP overexpression protects against endothelial cell (EC) damage, an intermediate end point for atherosclerosis. We bred apoE-knockout (apoE(-/-)) mice that were FRP+ transgenic (they overexpressed FRP). We compared them with control mice (their littermates). Human umbilical vein endothelial cells (HUVECs) were isolated and treated with ox-LDL and recombinant FRP. FRP-induced signal transduction and Bcl-2 mRNA and protein stability were analyzed. After 16 wk, apoE(-/-) FRP+ mice had significantly fewer apoptotic ECs than controls. In vitro experiments showed that the effect of FRP on EC apoptosis was mediated by upregulation of expression of the antiapoptotic protein Bcl-2. In HUVECs, FRP upregulated Bcl-2 transcription via a PI3K-Akt-NF-kappa B pathway. We conclude that FRP overexpression maintains EC viability by preventing apoptosis via Bcl-2 upregulation. FRP may be a novel therapeutic target for the prevention and treatment of vascular EC injury and of atherosclerosis.