Research Paper
Subject Category: Cardiovascular and pulmonary pharmacology
British Journal of Pharmacology (2008) 153, 1409–1419; doi:10.1038/bjp.2008.21; published online 18 February 2008
Agonists at PPAR-
suppress angiotensin II-induced production of plasminogen activator inhibitor-1 and extracellular matrix in rat cardiac fibroblasts
G-H Hao1,2, X-L Niu1,2, D-F Gao1, J Wei1 and N-P Wang3
- 1Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China
- 2Department of Cardiology, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi, China
- 3Department of Cardiology, Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, China
Correspondence: Professor X-L Niu, Department of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710004, China. E-mail: niuxl@mail.xjtu.edu.cn
Received 6 September 2007; Revised 14 November 2007; Accepted 21 December 2007; Published online 18 February 2008.
Abstract
Background and purpose:
Peroxisome proliferator-activated receptor (PPAR)-
ligands have been shown to inhibit cardiac fibrosis. However, the underlying mechanisms are poorly understood. We investigated the regulation by PPAR- ligands of angiotensin (Ang) II-induced plasminogen activator inhibitor (PAI)-1, extracellular matrix (ECM) production and cell growth in cardiac fibroblasts.
Experimental approach:
The effects of PPAR- ligands on Ang II-induced PAI-1, ECM expression and cell growth were assessed in primary-cultured rat cardiac fibroblasts; cardiac PAI-1 and ECM production was examined in Ang II-infused rats.
Key results:
In growth-arrested cardiac fibroblasts, PPAR- ligands rosiglitazone and 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) dose-dependently attenuated Ang II-induced cell proliferation and expression of PAI-1, collagen type-I, collagen type-III and fibronectin. An accompanying increase in PPAR- expression and activation was also observed. These suppressive effects were attenuated by the PPAR- antagonists GW9662 and bisphenol A diglycidyl ether (BADGE). Moreover, rosiglitazone and 15d-PGJ2 inhibited in part the expression and phosphorylation of Ang II-induced transforming growth factor (TGF)-
1, Smad2/3 and c-Jun NH(2)-terminal kinase (JNK). Ang II infusion in rats markedly increased left ventricular production of PAI-1, collagen and fibronectin, with a concurrent increase in the ratios of heart weight/body weight and left ventricle weight/body weight. Co-treatment with rosiglitazone significantly decreased these levels and upregulated PPAR- expression.
Conclusions and implications:
Rosiglitazone and 15d-PGJ2 suppress Ang II-induced production of PAI-1 and ECM probably via interactions between PPAR- and TGF-1/Smad2/3 and JNK signalling pathways. It is suggested that PPAR- and its ligands may have potential applications in preventing cardiac fibrosis.
Keywords:
PPAR-, angiotensin, cardiac fibroblast, plasminogen activator inhibitor-1, extracellular matrix, rosiglitazone, 15d-PGJ2, fibrosis
Abbreviations:
15d-PGJ2, 15-deoxy-12,14-prostaglandin J2; Ang II, angiotensin II; BADGE, bisphenol A diglycidyl ether; ECM, extracellular matrix; JNK, c-Jun NH(2)-terminal kinase; PAI-1, plasminogen activator inhibitor-1; PPAR-, peroxisome proliferator-activated receptor-; PPRE, PPAR-responsive element; TGF-1, transforming growth factor-1
