Doxorubicin-Induced Myocardial Fibrosis Involves the Neurokinin-1 Receptor and Direct Effects on Cardiac Fibroblasts.
Doxorubicin-Induced Myocardial Fibrosis Involves the Neurokinin-1 Receptor and Direct Effects on Cardiac Fibroblasts.
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DOI：
10.1016/j.hlc.2018.08.003
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发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
Meléndez GC
中科院分区：
文献类型：
--
作者：
Levick SP;Soto-Pantoja DR;Bi J;Hundley WG;Widiapradja A;Manteufel EJ;Bradshaw TW;Meléndez GC
接受蒽环类药物化疗（Anth-bC）的癌症患者可能会出现早期心脏纤维化，这可能是左心室（LV）功能受损的重要机制。P物质是一种主要通过神经激肽1受体（NK-1 R）发挥作用的神经肽，在其他心肌病中有助于不良心肌重塑和纤维化。我们试图确定NK-1 R阻断是否对阿霉素（Dox -一种常用的Anth-bC）诱导的心脏纤维化和心肌细胞凋亡有效。此外，我们探讨了Dox对心脏成纤维细胞的直接影响。雄性Sprague-Dawley大鼠随机接受生理盐水、6个周期的Dox（1.5 mg Dox/kg/周期）或Dox + NK-1 R拮抗剂（L732138，5 mg/kg/天，直至Dox治疗）。在首次剂量Dox后8周，评价LV功能和组织病理学心肌纤维化和细胞凋亡。在体外测量胶原分泌以测试心脏成纤维细胞的直接Dox活化。接受Dox治疗（9 mg/kg累积剂量）的大鼠出现心脏纤维化和心肌细胞凋亡。阻断NK-1 R部分减轻了心肌纤维化，同时完全防止了心肌细胞凋亡。这导致舒张功能改善。此外，我们发现Dox对心脏成纤维细胞有直接作用，导致胶原蛋白产生增加和细胞存活增加。这项研究表明，由Anth-bC诱导的心脏纤维化可以通过NK-1 R阻断来减少。残余纤维化反应可能是由于Dox对心脏成纤维细胞产生胶原的直接作用。
Cancer patients receiving anthracycline-based chemotherapy (Anth-bC) may experience early cardiac fibrosis, which could be an important contributing mechanism to the development of impaired left ventricular (LV) function. Substance P, a neuropeptide that predominantly acts via the neurokinin 1 receptor (NK-1R), contributes to adverse myocardial remodeling and fibrosis in other cardiomyopathies. We sought to determine if NK-1R blockade is effective against doxorubicin (Dox – a frequently used Anth-bC)-induced cardiac fibrosis and cardiomyocyte apoptosis. In addition, we explored the direct effects of Dox on cardiac fibroblasts. Male Sprague-Dawley rats were randomized to receive saline, six cycles of Dox (1.5 mg Dox/kg/cycle) or Dox with an NK-1R antagonist (L732138, 5 mg/kg/daily through Dox treatment). At 8 weeks after the initial dose of Dox, LV function and histopathological myocardial fibrosis and cell apoptosis were assessed. Collagen secretion was measured in vitro to test direct Dox activation of cardiac fibroblasts. Rats undergoing Dox treatment (9 mg/kg cumulative dose) developed cardiac fibrosis and cardiomyocyte apoptosis. NK-1R blockade partially mitigated cardiac fibrosis while completely preventing cardiomyocyte apoptosis. This resulted in improved diastolic function. Furthermore, we found that Dox had direct effects on cardiac fibroblasts to cause increased collagen production and enhanced cell survival. This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen.
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心脏MRI：一种用于表征蒽环类诱导心肌重塑的翻译成像工具。
影响因子：
4.7
作者：
Nguyen KL;Hu P;Ennis DB;Shao J;Pham KA;Chen JJ
通讯作者：
Chen JJ
影响因子：
24
作者：
Assomull, Ravi G.;Prasad, Sanjay K.;Pennell, Dudley J.
通讯作者：
Pennell, Dudley J.
影响因子：
--
作者：
Sweeney, Mark;Yiu, Angela;Lyon, Alexander R
通讯作者：
Lyon, Alexander R
影响因子：
2.8
作者：
Neilan, Tomas G.;Coelho-Filho, Otavio R.;Jerosch-Herold, Michael
通讯作者：
Jerosch-Herold, Michael
DOI：
10.1161/circimaging.115.004325
发表时间：
2016-08
期刊：
Circulation. Cardiovascular imaging
影响因子：
--
作者：
Jordan JH;Vasu S;Morgan TM;D'Agostino RB Jr;Meléndez GC;Hamilton CA;Arai AE;Liu S;Liu CY;Lima JA;Bluemke DA;Burke GL;Hundley WG
通讯作者：
Hundley WG