Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep40523
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Funding
- Natural Science Foundation of Shandong Province [ZR2014JL048, ZR2015HL125]
- National Natural Science Foundation of China [81503059, 81473188]
- Comprehensive Research Platform for Natural Medicine and New Formulation [2013ZX09402201002]
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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-alpha (LXR-alpha) expression. PFD attenuated body weight, heart weight, left ventricular weight, left ventricular systolic pressure, and +/- dp/dt(max) changes 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-alpha 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-alpha.
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