Inflammatory and fibrotic processes are involved in the cardiotoxic effect of sunitinib: Protective role of L-carnitine
Inflammatory and fibrotic processes are involved in the cardiotoxic effect of sunitinib: Protective role of L-carnitine
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DOI：
10.1016/j.toxlet.2015.11.007
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发表时间：
2016-01-22
影响因子：
3.5
通讯作者：
Vazquez, Carmen M.
中科院分区：
文献类型：
--
作者：
Blanca, Antonio J.;Ruiz-Armenta, Maria V.;Vazquez, Carmen M.
舒尼替尼(SU)目前被批准用于治疗几种恶性肿瘤。然而，在疾病稳定的同时，心血管毒性也得到了越来越多的认识。本研究的目的是分析苏的心脏毒性机制，并探讨L肉碱的潜在心脏保护作用。为此，Wistar大鼠分为四组：(1)对照组；(2)400 mg/kg/d组；(3)25 mg/kg/d组；(4)LC+SU组。此外，培养的大鼠心肌细胞用核因子-kappa B的抑制物(NF-kappa B)处理，以检测该转录因子在这一过程中的作用。SU处理组大鼠心肌促炎细胞因子表达增加，同时核因子-kappaB的mRNA表达增加。这些结果伴随着促纤维化因子、NADPH氧化酶的硝基酪氨酸和NOX-2亚单位的表达增加，而胶原降解因子的表达减少。SU处理的大鼠的血压和心率水平也更高。LC联合给药可抑制上述改变。此外，SU的心脏毒性作用可被抑制核因子-kappaB阻断。我们的结果提示：(I)炎症和纤维化过程参与了SU治疗后观察到的心脏毒性；(Ii)这些过程可能是由转录因子NF-kappa B介导的；(Iii)LC对动脉高压、心脏炎症和纤维化具有保护作用，这些都是SU治疗后观察到的。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of L-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400 mg LC/kg/day; (3) rats treated with 25 mg Su/kg/day; and (4) rats treated with LC + Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-kappa B), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-kappa B, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-kappa B inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-kappa B; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment. (C) 2015 Elsevier Ireland Ltd. All rights reserved.