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首页> 外文期刊>Cardiovascular toxicology >Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells
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Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

机译：丝裂原激活的蛋白激酶途径介导舒尼替尼诱导的大鼠心肌H9c2细胞肥大。

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Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor used for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Cardiotoxicity has been reported as a significant side effect associated with the SUN treatment, yet the mechanism is poorly understood. The main purpose of this study was to investigate the potential effects of SUN on cardiac hypertrophic genes and the role of mitogen-activated protein kinases (MAPKs) signaling pathway in rat cardiomyocyte H9c2 cell line. In the present study, real-time quantitative polymerase chain reaction showed that the treatment of H9c2 cells with increasing concentrations of SUN (0, 1, 2.5, and 5 A mu M) significantly induced hypertrophic gene markers, such as brain natriuretic peptides (BNP) and myosin heavy chain (beta-MHC and alpha-MHC) in concentration- and time-dependent manners. The onset of mRNA induction was observed as early as 9 h and remained elevated for at least 18 h after treatment with SUN 5 A mu M. At the protein level, Western blot analysis showed that SUN increased BNP and beta-MHC, while it inhibited alpha-MHC protein levels in a concentration-dependent manner. These SUN-mediated effects were associated with increase in cell size and hypertrophy by approximately 70 % at the highest concentration, 5 A mu M. Importantly, inhibition of the MAPK signaling pathway using SB203580 (p38 MAPK inhibitor), U0126 (extracellular signal-regulated kinase inhibitor), and SP600125 (c-Jun NH2-terminal kinase inhibitor) significantly potentiated the SUN-induced BNP and beta-MHC mRNA levels, but did alter the alpha-MHC level. Whereas at the protein level, MAPK inhibitors generally decreased the SUN-induced BNP, whereas only SB and U0 increased beta-MHC protein levels with no effect on alpha-MHC, which were associated with a significant decrease in cell size. Together, these results indicate that SUN induced hypertrophic gene expression through MAPK-dependent mechanisms.
机译：舒尼替尼（SUN）是一种多靶点酪氨酸激酶抑制剂，用于治疗胃肠道间质瘤和肾细胞癌。据报道，心脏毒性是与SUN治疗相关的重大副作用，但其机理尚不清楚。这项研究的主要目的是研究SUN对心肌肥大基因的潜在影响以及有丝分裂原激活的蛋白激酶（MAPKs）信号通路在大鼠心肌H9c2细胞系中的作用。在本研究中，实时定量聚合酶链反应显示，以浓度递增的SUN（0、1、2.5和5 AμM）处理H9c2细胞可显着诱导肥大性基因标记，例如脑钠肽（BNP）。 ）和肌球蛋白重链（β-MHC和α-MHC）的浓度和时间依赖性。在用SUN 5 AμM处理后，最早在9 h观察到了mRNA诱导的发作，并在至少18 h内保持升高。在蛋白质水平上，蛋白质印迹分析表明SUN增加了BNP和β-MHC，而抑制了α-MHC蛋白水平呈浓度依赖性。这些SUN介导的作用与最高浓度5 AμM的细胞大小和肥大增加约70％相关。重要的是，使用SB203580（p38 MAPK抑制剂），U0126（细胞外信号调节）抑制MAPK信号传导途径激酶抑制剂）和SP600125（c-Jun NH2末端激酶抑制剂）显着增强了SUN诱导的BNP和β-MHCmRNA水平，但确实改变了α-MHC水平。在蛋白质水平上，MAPK抑制剂通常会降低SUN诱导的BNP，而只有SB和U0会增加β-MHC蛋白水平，而对α-MHC没有影响，这与细胞大小的显着减少有关。总之，这些结果表明SUN通过MAPK依赖性机制诱导了肥大基因的表达。

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