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.

Authors:
Yanshen Li
Yanshen Li
Yantai University
Associated Professor
Beijing, Shandong | China

Sci Rep 2017 01 16;7:40523. Epub 2017 Jan 16.

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, P.R. China.

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/dt 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-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.

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http://dx.doi.org/10.1038/srep40523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5238375PMC
January 2017
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References

(Supplied by CrossRef)

N Li et al.
J Mol Cell Cardiol 2015

JF Ainscough et al.
Cardiovasc Res 2009

T Matsuo et al.
Sci Rep 2015

G Zhao et al.
J Huazhong Univ Sci Technolog Med Sci 2010

V Koka et al.
Am J Pathol 2008

L Xiao et al.
Am J Physiol Cell Physiol 2013

X Liu et al.
Heart Vessels 2016

MV Cannon et al.
EMBO Mol Med 2015

I Kuipers et al.
Lab Invest 2010

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