Anthracycline-induced suppression of GATA-4 transcription factor: Implication in the regulation of cardiac myocyte apoptosis
Anthracycline-induced suppression of GATA-4 transcription factor: Implication in the regulation of cardiac myocyte apoptosis
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DOI：
10.1124/mol.63.2.368
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发表时间：
2003-02-01
影响因子：
3.6
通讯作者：
Suzuki, YJ
中科院分区：
文献类型：
--
作者：
Kim, Y;Ma, AG;Suzuki, YJ
蒽环类药物是有效的癌症化疗药物，但会引起严重的心脏毒性。了解这些药物对心脏损害的机制将有助于开发更好的抗癌治疗策略。加塔-4转录因子是心肌细胞的重要调节因子。目前的研究表明，蒽环类药物可以下调加塔-4活性。用蒽环类药物如柔红霉素和阿霉素处理HL-1心肌细胞或分离的成年大鼠心室肌细胞，可降低加塔-4 DNA结合活性水平。加塔-4活性降低的机制作用于加塔-4基因水平，因为蒽环类药物导致加塔-4蛋白和mRNA水平显著降低。在放线菌素D存在下，加塔-4转录水平的下降速率不受蒽环类药物的影响，表明这些药物可能直接影响加塔-4基因的转录。为了确定降低的加塔-4水平是否在功能上与可由蒽环类药物诱导的心肌细胞死亡相关，测试了异位加塔因子拯救蒽环类药物诱导的细胞凋亡的能力。腺病毒介导的加塔-4或加塔-6的表达足以减弱细胞凋亡的发生率。此外，通过加塔-4的显性失活突变体抑制加塔-4 DNA结合活性可诱导凋亡。提示蒽环类药物对心肌细胞的毒性作用机制可能与下调加塔-4表达和诱导细胞凋亡有关。
Anthracyclines are effective cancer chemotherapeutic agents but can induce serious cardiotoxicity. Understanding the mechanism of cardiac damage by these agents will help in development of better therapeutic strategies against cancer. The GATA-4 transcription factor is an important regulator of cardiac muscle cells. The present study demonstrates that anthracyclines can down-regulate GATA-4 activity. Treatment of HL-1 cardiac muscle cells or isolated adult rat ventricular myocytes with anthracyclines such as daunorubicin and doxorubicin decreased the level of GATA-4 DNA-binding activity. The mechanism of decreased GATA-4 activity acts at the level of the GATA-4 gene, because anthracyclines caused significantly decreased levels of GATA-4 protein and mRNA. The rate of decline in GATA-4 transcript levels in the presence of actinomycin D was unaltered by anthracyclines, indicating that these agents may affect directly GATA-4 gene transcription. To determine whether decreased GATA-4 levels are functionally related to cardiac muscle cell death that can be induced by anthracyclines, the ability of ectopic GATA factors to rescue anthracycline-induced apoptosis was tested. Adenovirus-mediated expression of either GATA-4 or GATA-6 was sufficient to attenuate the incidence of apoptosis. Furthermore, suppression of GATA-4 DNA-binding activity by a dominant negative mutant of GATA-4 induced the apoptosis. These results suggest that the mechanism of anthracycline-induced cardiotoxicity may involve the down-regulation of GATA-4 and the induction of apoptosis.