In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Dec 2

PMID 22132230

Citations 52

Authors

Qiang Shi

Xiaoyan Liu

Yuanyuan Bai

Chuanjue Cui

Jun Li

Yishi Li

Shengshou Hu

Yingjie Wei

Affiliations

Soon will be listed here.

Abstract

Cardiac fibroblasts (CFs) are the primary cell type responsible for cardiac fibrosis during pathological myocardial remodeling. Several studies have illustrated that pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) attenuates cardiac fibrosis in different animal models. However, the effects of pirfenidone on cardiac fibroblast behavior have not been examined. In this study, we investigated whether pirfenidone directly modulates cardiac fibroblast behavior that is important in myocardial remodeling such as proliferation, myofibroblast differentiation, migration and cytokine secretion. Fibroblasts were isolated from neonatal rat hearts and bioassays were performed to determine the effects of pirfenidone on fibroblast function. We demonstrated that treatment of CFs with pirfenidone resulted in decreased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen contractility. Boyden chamber assay illustrated that pirfenidone inhibited fibroblast migration ability, probably by decreasing the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1. Furthermore, pirfenidone attenuated the synthesis and secretion of transforming growth factor-β1 but elevated that of interleukin-10. These direct and pleiotropic effects of pirfenidone on cardiac fibroblasts point to its potential use in the treatment of adverse myocardial remodeling.

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References

Eghbali M . Cardiac fibroblasts: function, regulation of gene expression, and phenotypic modulation. Basic Res Cardiol. 1992; 87 Suppl 2:183-9. DOI: 10.1007/978-3-642-72477-0_16. View

Brown R, Ambler S, Mitchell M, Long C . The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. Annu Rev Pharmacol Toxicol. 2005; 45:657-87. DOI: 10.1146/annurev.pharmtox.45.120403.095802. View

Rohde L, Ducharme A, Arroyo L, Aikawa M, Sukhova G, McClure K . Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation. 1999; 99(23):3063-70. DOI: 10.1161/01.cir.99.23.3063. View

Dosanjh A, Wan B, Throndset W, Sherwood S, Morris R . Pirfenidone: a novel antifibrotic agent with implications for the treatment of obliterative bronchiolitis. Transplant Proc. 1998; 30(5):1910-1. DOI: 10.1016/s0041-1345(98)00478-3. View

Leh S, Vaagnes O, Margolin S, Iversen B, Forslund T . Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats. Nephrol Dial Transplant. 2004; 20(1):71-82. DOI: 10.1093/ndt/gfh562. View

Nakazato H, Oku H, Yamane S, Tsuruta Y, Suzuki R . A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. Eur J Pharmacol. 2002; 446(1-3):177-85. DOI: 10.1016/s0014-2999(02)01758-2. View

Porter K, Turner N . Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther. 2009; 123(2):255-78. DOI: 10.1016/j.pharmthera.2009.05.002. View

Lu B, Mahmud H, Maass A, Yu B, van Gilst W, de Boer R . The Plk1 inhibitor BI 2536 temporarily arrests primary cardiac fibroblasts in mitosis and generates aneuploidy in vitro. PLoS One. 2010; 5(9):e12963. PMC: 2945759. DOI: 10.1371/journal.pone.0012963. View

Lee K, Everett 4th T, Rahmutula D, Guerra J, Wilson E, Ding C . Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation. 2006; 114(16):1703-12. PMC: 2129103. DOI: 10.1161/CIRCULATIONAHA.106.624320. View

10.

Li Z, Wei H, Deng L, Cong X, Chen X . Expression and secretion of interleukin-1β, tumour necrosis factor-α and interleukin-10 by hypoxia- and serum-deprivation-stimulated mesenchymal stem cells. FEBS J. 2010; 277(18):3688-98. DOI: 10.1111/j.1742-4658.2010.07770.x. View

11.

Visner G, Liu F, Bizargity P, Liu H, Liu K, Yang J . Pirfenidone inhibits T-cell activation, proliferation, cytokine and chemokine production, and host alloresponses. Transplantation. 2009; 88(3):330-8. PMC: 2726969. DOI: 10.1097/TP.0b013e3181ae3392. View

12.

Gurtner G, Werner S, Barrandon Y, Longaker M . Wound repair and regeneration. Nature. 2008; 453(7193):314-21. DOI: 10.1038/nature07039. View

13.

Miric G, Dallemagne C, Endre Z, Margolin S, Taylor S, Brown L . Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol. 2001; 133(5):687-94. PMC: 1572838. DOI: 10.1038/sj.bjp.0704131. View

14.

Nguyen D, Ding C, Wilson E, Marcus G, Olgin J . Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart Rhythm. 2010; 7(10):1438-45. DOI: 10.1016/j.hrthm.2010.04.030. View

15.

Lijnen P, Petrov V, Rumilla K, Fagard R . Transforming growth factor-beta 1 promotes contraction of collagen gel by cardiac fibroblasts through their differentiation into myofibroblasts. Methods Find Exp Clin Pharmacol. 2003; 25(2):79-86. DOI: 10.1358/mf.2003.25.2.723680. View

16.

Hewitson T, Kelynack K, Tait M, Martic M, Jones C, Margolin S . Pirfenidone reduces in vitro rat renal fibroblast activation and mitogenesis. J Nephrol. 2002; 14(6):453-60. View

17.

Porter K, Naik J, Turner N, Dickinson T, Thompson M, London N . Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration. J Vasc Surg. 2002; 36(1):150-7. DOI: 10.1067/mva.2002.122029. View

18.

Burghardt I, Tritschler F, Opitz C, Frank B, Weller M, Wick W . Pirfenidone inhibits TGF-beta expression in malignant glioma cells. Biochem Biophys Res Commun. 2007; 354(2):542-7. DOI: 10.1016/j.bbrc.2007.01.012. View

19.

Wilson M, Elnekave E, Mentink-Kane M, Hodges M, Pesce J, Ramalingam T . IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice. J Clin Invest. 2007; 117(10):2941-51. PMC: 1978425. DOI: 10.1172/JCI31546. View

20.

Wilson E, Gunasinghe H, Coker M, Sprunger P, Lee-Jackson D, Bozkurt B . Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure. J Card Fail. 2003; 8(6):390-8. DOI: 10.1054/jcaf.2002.129659. View