Down-regulation of cardiac lineage protein (CLP-1) expression in CLP-1+/- mice affords cardioprotection against ischaemic stress
Down-regulation of cardiac lineage protein (CLP-1) expression in CLP-1+/- mice affords cardioprotection against ischaemic stress
复制标题
DOI：
10.1111/j.1582-4934.2008.00404.x
复制
发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Siddiqui, M. A. Q.
中科院分区：
文献类型：
--
作者：
Mascareno, Eduardo;Manukyan, Irena;Siddiqui, M. A. Q.
为了了解细胞对应激保护的转录机制，我们评估了已知的转录延伸复合体(PTEFb)抑制物CLP-1在CLP-1+/-小鼠心脏中的作用。使用离体心模型，我们观察到CLP-1+/-心脏在受到缺血应激并通过血流动力学测量进行评估时，表现出显著的心脏保护作用。在杂合子心脏中，CLP-1仍然与pTEFb复合体相关，而在野生型心脏中，CLP-1被释放，这表明pTEFb调控参与了细胞保护。在CLP-1+/-心脏中，CDK7和CDK9的活性降低，进而降低了Pol II CTD的丝氨酸-5和丝氨酸-2的磷酸化。然而，与同样处理的野生型CLP-1+/+心脏相比，受到缺血应激的CLP-1+/-心脏线粒体蛋白PGC-1α和HIF-1α的水平增加，这两种蛋白增强线粒体活性并与细胞存活有关。丙酮酸脱氢酶激酶(PDK-1)的表达也增加，这有助于细胞对低氧应激的适应。综上所述，我们的数据表明，CLP-1水平的调节对于生存计划的细胞适应至关重要，生存计划保护心肌细胞免受应激的共同作用，这是由于RNA Pol II磷酸化降低，但调节线粒体功能和代谢适应应激的靶蛋白表达增加。
In order to understand the transcriptional mechanism that underlies cell protection to stress, we evaluated the role of CLP-1, a known inhibitor of the transcription elongation complex (pTEFb), in CLP-1 +/- mice hearts. Using the isolated heart model, we observed that the CLP-1+/- hearts, when subjected to ischaemic stress and evaluated by haemodynamic measurements, exhibit significant cardioprotection. CLP-1 remains associated with the pTEFb complex in the heterozygous hearts, where as it is released in the wild-type hearts suggesting the involvement of pTEFb regulation in cell protection. There was a decrease in Cdk7 and Cdk9 kinase activity and consequently in phosphorylation of serine-5 and serine-2 of Pol II CTD in CLP-1 +/- hearts. However, the levels of mitochondrial proteins, PGC-1 alpha and HIF-1 alpha, which enhance mitochondrial activity and are implicated in cell survival, were increased in CLP-1+/- hearts subjected to ischaemic stress compared to that in wild-type CLP-1+/+ hearts treated identically. There was also an increase in the expression of pyruvate dehydrogenase kinase (PDK-1), which facilitates cell adaptation to hypoxic stress. Taken together, our data suggest that regulation of the CLP-1 levels is critical to cellular adaptation of the survival program that protects cardiomyocytes against stress due collectively to a decrease in RNA Pol II phosphorylation but an increase in expression of target proteins that regulate mitochondrial function and metabolic adaptation to stress.