Cardioprotection of voluntary exercise against breast cancer-induced cardiac injury via STAT3.

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Lan Wu, Zhi-Zheng Li, Hao Yang, Li-Zhi Cao, Xiao-Ying Wang, Dong-Liang Wang, Emeli Chatterjee, Yan-Fei Li, Gang Huang
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Abstract

Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.

Abstract Image

自愿运动通过 STAT3 对乳腺癌诱发的心脏损伤起到保护作用
运动是在一定程度上缓解乳腺癌诱发的心脏损伤的有效方法。然而,自主运动(VE)是否能激活心脏信号转导子和转录激活子3(STAT3)及其内在机制仍不清楚。本研究探讨了STAT3-microRNA(miRNA)-靶向蛋白轴在VE对抗乳腺癌诱导的心脏损伤中的作用。与未患乳腺癌的同窝小鼠(MMTV-PyMT -)相比,持续4周的VE不仅能改善转基因乳腺癌雌性小鼠[小鼠乳腺肿瘤病毒-多瘤病毒中间T抗原(MMTV-PyMT +)]的心脏功能,还能增加心肌STAT3酪氨酸705磷酸化。与 MMTV-PyMT - 小鼠相比,MMTV-PyMT + 小鼠的心肌纤维化更明显,心肌细胞体积更小,细胞存活率更低,血清肿瘤坏死因子(TNF)-α更高。然而,VE并不影响肿瘤的生长。MiRNA 测序发现,在 VE 诱导的心肌保护中,miR-181a-5p 上调,miR-130b-3p 下调。心肌注射驱动STAT3酪氨酸705突变的9号血清型腺相关病毒后,上述心脏保护作用消失。在离体心肌细胞中,心肌 STAT3 被确定为结合 pri-miR-181a(miR-181a-5p 的前体)和 HOX 转录本反义 RNA(HOTAIR,海绵状 miR-130b-3p)启动子的转录因子。此外,在 AC-16 细胞中还证实了靶向 PTEN 的 miR-181a-5p 和靶向锌指和含 BTB 结构域蛋白 20(Zbtb20)的 miR-130b-3p。这些研究结果表明,VE通过激活STAT3促进靶向PTEN的miR-181a-5p和促进HOTAIR海绵化靶向Zbtb20的miR-130b-3p来保护乳腺癌诱导的心脏损伤,有助于开发运动疗法治疗乳腺癌诱导的心脏损伤的新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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