Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction
Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction
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DOI：
10.1161/01.res.0000220106.64661.71
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发表时间：
2006-05-12
影响因子：
20.1
通讯作者：
Kolattukudy, Pappachan E.
中科院分区：
文献类型：
--
作者：
Zhou, Limei;Azfer, Asim;Kolattukudy, Pappachan E.
单核细胞趋化蛋白-1（MCP- 1; CCL 2）介导的炎症在缺血性心脏病（IHD）的发展中起着关键作用。然而，由MCP- 1与其受体CCR 2结合引发的信号转导引起的基因表达变化及其在IHD发展中的可能作用尚不清楚。我们提出的证据表明，MCP- 1结合CCR 2诱导一种新的转录因子（MCP诱导蛋白[ MCPIP]），导致细胞死亡。基因芯片分析表明，当在人胚肾293细胞中表达时，MCPIP在引起细胞死亡之前诱导凋亡基因家族。诱变研究表明，转录因子样活性所需的结构特征也是导致细胞死亡所必需的。在MCPIP转染后检测到caspase- 3的活化，Z-VAD-favorin部分抑制细胞死亡.小鼠心肌细胞靶向表达MCP- 1导致6月龄时心力衰竭死亡。MCPIP表达增加与心室功能障碍的发展平行。原位杂交显示心肌细胞中存在MCPIP转录本，免疫组织化学显示MCPIP与凋亡心肌细胞的心肌细胞核相关。心肌细胞中CCR 2的表达随缺血再灌注的加重而增加。在该小鼠模型中，由MCP- 1与心肌细胞中的CCR 2结合诱导的MCPIP产生可能参与了IHD的发展。与非缺血性心脏病患者相比，IHD患者的MCPIP转录水平更高。这些结果为慢性炎症和暴露于MCP- 1如何导致心力衰竭提供了分子见解，并表明MCPIP可能是治疗干预的潜在靶点。
Monocyte chemoattractant protein- 1 ( MCP- 1; CCL2) - mediated inflammation plays a critical role in the development of ischemic heart disease ( IHD). However, the gene expression changes caused by signal transduction, triggered by MCP- 1 binding to its receptor CCR2, and their possible role in the development of IHD are not understood. We present evidence that MCP- 1 binding to CCR2 induces a novel transcription factor ( MCP- induced protein [ MCPIP]) that causes cell death. Gene microarray analysis showed that when expressed in human embryonic kidney 293 cells, MCPIP induced apoptotic gene families before causing cell death. Mutagenesis studies showed that the structural features required for transcription factor - like activity were also required for causing cell death. Activation of caspase- 3 was detected after MCPIP transfection and Z- VAD- fmk partially inhibited cell death. Cardiomyocyte- targeted expression of MCP- 1 in mice caused death by heart failure at 6 months of age. MCPIP expression increased in parallel with the development of ventricular dysfunction. In situ hybridization showed the presence of MCPIP transcripts in the cardiomyocytes and immunohistochemistry showed that MCPIP was associated with the cardiomyocyte nuclei of apoptotic cardiomyocytes. CCR2 expression in cardiomyocytes increased with the development of IHD. MCPIP production induced by MCP- 1 binding to CCR2 in the cardiomyocytes is probably involved in the development of IHD in this murine model. MCPIP transcript levels were much higher in the explanted human hearts with IHD than with nonischemic heart disease. These results provide a molecular insight into how chronic inflammation and exposure to MCP- 1 contributes to heart failure and suggest that MCPIP could be a potential target for therapeutic intervention.