Doxorubicin Induces Apoptosis in H9c2 Cardiomyocytes: Role of Overexpressed Eukaryotic Translation Initiation Factor 5A

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概要

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• The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of solid tumors and malignant hematologic disease. Although the mechanism by which it causes cardiac injury is not yet known, apoptosis has been regarded as one of mechanisms underlying the cardiotoxic effects of doxorubicin. Eukaryotic translation initiation factor 5A (eIF5A) is a ubiquitously expressed multifunctional protein that interacts with a range of ligands and is implicated in cell signaling. However, there has been no direct evidence for the critical involvement of eIF5A in doxorubicin-induced apoptosis. Overexpression of eIF5A induced by doxorubicin in cardiomyocyte leads to growth perturbation along with initiation of apoptosis. Overexpression of eIF5A results in a gradual increase in reactive oxygen species (ROS) generation. This mitochondrial dysfunction is due to a gradual increase in ROS generation in eIF5A-overexpressing H9c2 cells. Along with ROS generation, increased Ca2+ influx in mitochondria leads to loss of the mitochondrial transmembrane potential, release of cytochrome-c, and caspase activation. However, small interfering RNA (siRNA)-mediated suppression of eIF5A results in inhibition of apoptosis. Interestingly, upon overexpression of eIF5A induced by doxorubicin, cell apoptosis was shown to be significantly inhibited when cells were treated with SB202190 (p38 mitogen-activated protein kinase inhibitor) and SP600125 (anti-c-Jun N-terminal kinase inhibitor) for 18 h. The reduction in oxidant generation and reduction in the apoptotic cell population were the results of the disruption of eIF5A expression, corroborating the hypothesis that excess ROS generation with overexpression of eIF5A induced by doxorubicin leads to apoptosis due to the accumulation of eIF5A.

著者

• Yang Zhi-jian

  Department Of Cardiology First Affiliated Hospital Of Nanjing Medical University

• Zhu Rong

  Department Of Pathology Shanghai Medical College Fudan University

• LU Xiang

  Department of Cardiology, Jiangsu Province Hospital, Nanjing Medical University

• Tan Xiao

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

• Wang Di-bin

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

• Wei Hui

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

• Zhu Shu-shu

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

• Jiang Hai

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

• Lu Xiang

  Department Of Biological Engineering Nanjing Forestry University

• Lu Xiang

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

• Yang Zhi-jian

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

• Zhu Rong

  Department of Cardiology, Second Clinical Medical School of Nanjing Medical University

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