PEX1抑制阿霉素诱导心肌细胞凋亡的机制研究

Doxorubicin (DOX), an anthracyclic antineoplastic agent, is one of the most commonly chemotherapeutic drug utilized to treat a variety of human tumors, but cardiotoxicity as a major factor limiting its clinical use. Cardiomyocytes with phenylephrine-induced complex-1 (PEX1) upregulated have an effect on inhibition of DOX induced apoptosis, however, the molecular components and detailed mechanisms remain largely unidentified. PEX1, a new member of the Kru¨ppel family, is essential for α1-adrenergic action which have been proved to attenuate cardiomyocytes apoptosis by manipulating GATA-4 activity. In our preliminary experiments, we detected the Pex1+/- mice have less GATA4 expression in the heart, furthermore, compared to the WT mice, significantly reduced heart function and more interstitial Fibrosis formation were detected in Pex1+/- mice when treated with DOX. To further illustrate the regulatory role and mechanisms of PEX1 in inhibition of DOX-induced cardiomyocytes apoptosis, the following experiments will be performed: (1) Investigation the change of PEX1 expression during DOX-induced cardiomyocyets apoptosis; (2) Elucidate the role of PEX1 in inhibition of DOX-induced cardiomyocyets ; (3) Illustration PEX1 promote α1-adrenergic signaling pathway to increase GATA4 expression and inhibit the cardiomyocytes apoptosis. This study may provide a feasibility for the successful treatment of DOX cardiomyotoxity.

阿霉素(DOX)是常用的抗肿瘤药物，其心脏毒性严重限制临床使用。研究表明，心肌细胞中转录因子PEX1表达增加可抑制DOX诱导的细胞凋亡，但是其机制尚未明确。PEX1是α1-肾上腺素能信号通路的枢纽，该信号通路通过促进GATA4表达，抑制心肌细胞凋亡。我们前期在Pex1+/-小鼠中发现心肌细胞GATA4表达降低；与对照相比，经DOX处理后Pex1+/-小鼠心脏功能显著下降，心肌细胞间大量纤维结缔组织形成。为了阐明PEX1抑制DOX诱导心肌细胞凋亡的机制，我们将研究：（1）PEX1在DOX诱导心肌细胞凋亡中的表达变化；（2）通过抑制或过表达PEX1明确PEX1抑制DOX诱导心肌细胞凋亡的作用；（3）PEX1通过促进α1-肾上腺素能核内信号通路下游靶基因GATA4表达抑制DOX诱导心肌细胞凋亡的机制。本研究有望从促进心肌内源性保护潜能的角度对DOX心脏毒性制定有效防治策略。

阿霉素(DOX)是常用的抗肿瘤药物，其心脏毒性严重限制临床使用。研究表明，心肌细胞中转录因子PEX1表达增加可抑制DOX诱导的细胞凋亡，但是其机制尚未明确。PEX1是α1-肾上腺素能信号通路的枢纽，该信号通路通过促进GATA4表达，抑制心肌细胞凋亡。我们前期在Pex1+/-小鼠中发现心肌细胞GATA4表达降低；与对照相比，经DOX处理后Pex1+/-小鼠心脏功能显著下降，心肌细胞间大量纤维结缔组织形成。本研究通过体内外研究证实Pex1表达减少可加重DOX诱导的心肌细胞凋亡，而构建慢病毒使原代心肌细胞中Pex1表达增加，可明显缓解DOX诱导的心肌细胞凋亡，提示PEX1可抑制DOX诱导的心肌细胞凋亡；进一步研究其机制中确认PEX1通过促进α1-肾上腺素能核内信号通路从而减少DOX诱导心肌细胞凋亡，而GATA4可能是PEX1通过促进该信号通路的下游重要靶基因。本研究有望从促进心肌内源性保护潜能的角度对DOX心脏毒性制定有效防治策略。