Journal
EXPERIMENTAL AND MOLECULAR PATHOLOGY
Volume 87, Issue 3, Pages 212-218Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yexmp.2009.06.001
Keywords
Interleukin-17; Isoproterenol-induced heart failure; Myocardial fibrosis; Matrix metalloproteinase; Tissue inhibitor of metalloproteinase; Osteoprotegerin; Receptor activator of nuclear factor-kappa B ligand; Collagens
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Funding
- National 973 project
- the youth special science and technology foundation in Heilongjiang Province
- Doctoral scientific foundation of the first affiliated hospital of Harbin Medical University [2007033]
- Doctor foundation of the Ministry of Education [20070226005]
- Heilongjiang Education Bureau [11531171]
- NSFC [30800481]
- [ZJY0707-01]
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Objective: This study was designed to investigate whether IL-17 can regulate the expression of the MMP/TIMP system, the OPG/RANK/RANKL system, or type-I and type-III collagen fibers in a rat model of isoproterenol-induced heart failure (HF). We also investigated the effect of IL-17 on myocardial fibrosis in this model. Methods: HF was induced in Wistar-Kyoto rats by hypodermic injection of isoproterenol (ISO) twice every 24 h. After 2 months, the surviving rats were divided into three groups: monoclonal Anti-IL-17 Ab (100 mu g/day), IgG (100 mu g/day) or PBS were injected five times every 48 h (i.p.). One day after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluate myocardial fibrosis, and immunohistochemistry was used to measure the levels of MMP-1, TIMP-1, TIMP-4, OPG, RANKL, type-I and type-III collagen fibers. We also treated adult rat cardiac fibroblasts with IL-17 (10 ng/ml), IL-17 (10 ng/ml) + OPG (10 ng/ml), IL-17 (10 ng/ml) + anti-RANKL Ab (100 ng/ml), or PBS for 24 h, realtime RT-PCR was used to measure the expressions of MMP-1. Results: The expressions of MMP-1, RANKL, and type-I and -III collagen fibers decreased, and the expressions of TIMP-1, TIMP-4, and OPG increased in the Anti-IL-17 group compared to controls. H&E and Masson staining revealed that blockade of IL-17 can improve myocardial fibrosis in HE IL-17 increased the expression of MMP-1 in cardiac fibroblasts, and OPG and anti-IL-17 Ab could inhibit this function partly. Thus, IL-17 was dependent on the RANKL/OPG system to induce MMP-1 partly. Conclusion: Our study demonstrates the contribution of IL-17 to myocardial fibrosis in isoproterenol-induced HE IL-17 can regulate the RANKL/OPG and MMP/TIMP systems in this model. The RANKL/OPG system is one of intermediaries between IL-17 and MMP-1 in cardiac fibroblasts. As a harmful cytokine, anti-IL-17 treatment is a potential therapeutic strategy in HF. (C) 2009 Published by Elsevier Inc.
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