Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca2+-ATPase 2 gene transcription through modification of Sp1 binding
Carvedilol effectively blocks oxidative stress-mediated downregulation of sarcoplasmic reticulum Ca2+-ATPase 2 gene transcription through modification of Sp1 binding
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DOI：
10.1016/j.bbrc.2004.12.139
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发表时间：
2005-03-04
影响因子：
3.1
通讯作者：
Kurabayashi, M
中科院分区：
文献类型：
--
作者：
Koitabashi, N;Arai, M;Kurabayashi, M
卡维地洛是一种β-肾上腺素受体阻滞剂和有效的抗氧化剂，可改善心力衰竭患者的心功能。肌浆网Ca ~（2+）-ATPasc（SERCA 2）基因表达的恢复可能是其对心功能有益作用的潜在机制。在原代培养的新生大鼠心肌细胞中，卡维地洛或其P受体失活代谢产物BM 910228可减弱过氧化氢介导的SERCA 2 mRNA和蛋白水平的降低，而美托洛尔（一种纯β受体阻滞剂）则无此作用。此外，卡维地洛本身显著增强SERCA 2基因转录，表明卡维地洛特异性恢复SERCA 2基因转录。定点突变显示，在SERCA 2基因启动子区的两个Sp1位点介导的反应，卡维地洛氧化应激。此外，电泳迁移率变动分析显示，Sp1和Sp3转录因子与卡维地洛介导的变化，在启动子测定。这些研究可能为卡维地洛在心力衰竭中的有益作用提供了机制解释。(C)2005年爱思唯尔公司All rights reserved.
Carvedilol is a P-adrenoceptor blocker and a potent antioxidant that improves cardiac function in patients with heart failure. The restoration of sarcoplasmic reticulum Ca2+-ATPasc (SERCA2) gene expression may be an underlying mechanism of its beneficial effects on cardiac function. In primary cultured neonatal rat cardiac rnyocytes, treatment with either carvedilol or its P-receptor inactive metabolite, BM910228, attenuated the hydrogen peroxide-mediated decrease in SERCA2 mRNA and protein levels, while metoprolol, a pure beta-blocker, had no effect. Moreover, carvedilol itself significantly enhanced SERCA2 gene transcription, suggesting that carvedilol specifically restores SERCA2 gene transcription. Site-directed mutagenesis revealed that two Sp1 sites in the SERCA2 gene promoter region mediated the response to carvedilol under oxidative stress. Further, electrophoretic mobility shift assays revealed that Sp1 and Sp3 transcription factors correlated with carvedilol-mediated changes in the promoter assays. These studies may provide a mechanistic explanation for the beneficial effects of carvedilol in heart failure. (C) 2005 Elsevier Inc. All rights reserved.