Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis.
Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis.
复制标题
吡非尼酮通过调节心肌梗死引起的心脏纤维化中的肝脏 X 受体-α 来控制 AT1R/p38 MAPK/肾素-血管紧张素系统轴的反馈环路
DOI：
10.1038/srep40523
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发表时间：
2017-01-16
影响因子：
4.6
通讯作者：
Tian J
中科院分区：
文献类型：
--
作者：
Li C;Han R;Kang L;Wang J;Gao Y;Li Y;He J;Tian J
吡非尼酮（PFD）是一种抗纤维化的小分子药物，用于治疗纤维化疾病，但其对心肌梗死（MI）诱导的心脏纤维化的影响尚不清楚。本研究的目的是确定PFD对MI诱导的大鼠心脏纤维化的影响及其可能的机制。模型建立后，动物灌胃给予PFD 4周。在MI诱导的心脏纤维化的发展过程中，我们发现血管紧张素II 1型受体（AT 1 R）/磷酸化p38丝裂原活化蛋白激酶（p38 MAPK）通路与肾素-血管紧张素系统（RAS）之间的正反馈环被激活，并伴随肝脏X受体-α（LXR-α）表达的下调。PFD可减轻MI引起的体重、心脏重量、左心室重量、左心室收缩压和±dp/dtmax变化，这些变化与心肌纤维化、梗死面积和羟脯氨酸浓度的减少有关。此外，PFD抑制AT 1 R/p38 MAPK通路，纠正RAS失衡[降低血管紧张素转换酶（ACE）、血管紧张素II和血管紧张素II 1型受体表达，但增加ACE 2和血管紧张素（1-7）活性和Mas表达]，并强烈增强心脏LXR-α表达。这些结果表明，PFD的心脏保护作用可能在很大程度上是由于通过激活LXR-α来控制AT 1 R/p38 MAPK/RAS轴的反馈回路。
Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin-angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-α (LXR-α) expression. PFD attenuated body weight, heart weight, left ventricular weight, left ventricular systolic pressure, and ±dp/dtmaxchanges induced by MI, which were associated with a reduction in cardiac fibrosis, infarct size, and hydroxyproline concentration. Moreover, PFD inhibited the AT1R/p38 MAPK pathway, corrected the RAS imbalance [decreased angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II type 1 receptor expression, but increased ACE2 and angiotensin (1-7) activity and Mas expression] and strongly enhanced heart LXR-α expression. These results indicate that the cardioprotective effects of PFD may be due, in large part, to controlling the feedback loop of the AT1R/p38 MAPK/RAS axis by activation of LXR-α.