title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Han
authors.affiliation: School of Life Sciences, Yantai University, Yantai, 264005, P.R. China.
authors.forename: Le
authors.initials: L
authors.lastname: Kang
authors.affiliation: Yantai yuhuangding Hospital, Yantai, 264005, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Yantai University, Yantai, 264005, P.R. China.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: School of Life Sciences, Yantai University, Yantai, 264005, P.R. China.
authors.forename: Yanshen
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Life Sciences, Yantai University, Yantai, 264005, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.affiliation: 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.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Tian
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D025461:Feedback, Physiological; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D000071518:Liver X Receptors / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D018754:Ventricular Dysfunction / Q000150:complications / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D000071518:Liver X Receptors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; C093844:pirfenidone; D048051:p38 Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; D006909:Hydroxyproline