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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Heat shock factor-1 knockout induces multidrug resistance gene, MDFMb, and enhances P-glycoprotein (ABCB1)-based drug extrusion in the heart
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Heat shock factor-1 knockout induces multidrug resistance gene, MDFMb, and enhances P-glycoprotein (ABCB1)-based drug extrusion in the heart

机译：热休克因子-1基因敲除诱导多药耐药基因MDFMb，并增强心脏中基于P-糖蛋白（ABCB1）的药物挤出

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摘要

Heat-shock factor 1 (HSF-1), a transcription factor for heat-shock proteins (HSPs), is known to interfere with the transcriptional activity of many oncogenic factors. In the present work, we have discovered that HSF-1 ablation induced the multidrug resistance gene, MDR1b, in the heart and increased the expression of P-glycoprotein (P-gp, ABCB1), an ATP binding cassette that is usually associated with multidrug-resistant cancer cells. The increase in P-gp enhanced the extrusion of doxorubicin (Dox) to alleviate Dox-induced heart failure and reduce mortality in mice. Dox-induced left ventricular (LV) dysfunction was significantly reduced in HSF-1~(-/-) mice. DNA-binding activity of NF-kB was higher in HSF-1~(-/-)mice. IkB, the NF-kB inhibitor, was depleted due to enhanced IkB kinase (IKK)-α activity. In parallel, MDR1b gene expression and a large increase in P-gp and lowering Dox loading were observed in HSF-1~(-/-) mouse hearts. Moreover, application of the P-gp antagonist, verapamil, increased Dox loading in HSF-1~(-/-) cardiomyocytes, deteriorated cardiac function in HSF-1~(-/-) mice, and decreased survival. MDR1 promoter activity was higher in HSF-1~(-/-) cardiomyocytes, whereas a mutant MDR1 promoter with heat-shock element (HSE) mutation showed increased activity only in HSF-1~(+/+)cardiomyocytes. However, deletion of HSE and NF-kB binding sites diminished luminescence in both HSF-1~(+/+) and HSF-1~(-/-)cardiomyocytes, suggesting that HSF-1 inhibits MDR1 activity in the heart. Thus, because high levels of HSF-1 are attributed to poor prognosis of cancer, systemic down-regulation of HSF-1 before chemotherapy is a potential therapeutic approach to ameliorate the chemotherapy-induced cardio-toxicity and enhance cancer prognosis.
机译：热休克因子1（HSF-1）是热休克蛋白（HSP）的转录因子，已知会干扰许多致癌因子的转录活性。在目前的工作中，我们发现HSF-1切除可在心脏中诱导多药耐药基因MDR1b，并增加P-糖蛋白（P-gp，ABCB1）的表达，P-糖蛋白是一种通常与多药相关的ATP结合盒抗性癌细胞。 P-gp的增加增强了阿霉素（Dox）的挤出，从而减轻了Dox引起的心力衰竭并降低了小鼠的死亡率。在HSF-1〜（-/-）小鼠中，Dox引起的左心室（LV）功能障碍明显减少。 HSF-1〜（-/-）小鼠NF-κB的DNA结合活性较高。由于增强的IkB激酶（IKK）-α活性，耗尽了NF-kB抑制剂IkB。同时，在HSF-1〜（-/-）小鼠心脏中观察到了MDR1b基因的表达以及P-gp的大量增加和Dox负荷的降低。此外，使用P-gp拮抗剂维拉帕米会增加HSF-1〜（-/-）心肌细胞的Dox负荷，HSF-1〜（-/-）小鼠的心脏功能恶化，并降低存活率。 MDR1启动子活性在HSF-1〜（-/-）心肌细胞中较高，而具有热休克元件（HSE）突变的突变MDR1启动子仅在HSF-1〜（+ / +）心肌细胞中显示增加的活性。然而，HSE和NF-kB结合位点的缺失减少了HSF-1〜（+ / +）和HSF-1〜（-/-）心肌细胞的发光，表明HSF-1抑制了心脏中的MDR1活性。因此，由于高水平的HSF-1归因于癌症的预后不良，因此化疗前HSF-1的系统性下调是改善化疗诱导的心脏毒性和增强癌症预后的潜在治疗方法。

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  • 作者

    Karthikeyan Krishnamurthy; Kaushik Vedam; Ragu Kanagasabai; Lawrence J. Druhan; Govindasamy llangovan;

  • 作者单位

    Departments of lnternal Medicine, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210;

    Departments of lnternal Medicine, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210;

    Departments of lnternal Medicine, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210;

    Departments of Anesthesiology, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210;

    Departments of lnternal Medicine, Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    dilated cardiomyopathy; oxidative stress; mouse model of; cardioprotection; chemotherapeutics;

    机译：扩张型心肌病氧化应激鼠标模型心脏保护;化学疗法;

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