Journal
MATRIX BIOLOGY
Volume 29, Issue 7, Pages 613-620Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.matbio.2010.06.007
Keywords
Interleukin-1; Matrix metalloproteinase; Cardiac fibroblast; Extracellular matrix; p38 MAP kinase; Microarray
Categories
Funding
- British Heart Foundation [PG/06/012/20287]
- Research Councils UK
- Medical Research Council [G9900991B] Funding Source: researchfish
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The proinflammatory cytokine interleukin-1 (IL-1) elicits catabolic effects on the myocardial extracellular matrix (ECM) early after myocardial infarction but there is little understanding of its direct effects on cardiac myofibroblasts (CMF), or the role of p38 mitogen-activated protein kinase (MAPK). We used a focused RTPCR microarray to investigate the effects of IL-1 alpha on expression of 41 ECM genes in CMF cultured from different patients, and explored regulation by p38 MAPK. IL-1 alpha (10 ng/ml, 6 h) had minimal effect on mRNA expression of structural ECM proteins, including collagens, laminins, fibronectin and vitronectin. However, it induced marked increases in expression of specific ECM proteases, including matrix metalloproteinases MMP-1 (collagenase-1), MMP-3 (stromelysin-1), MMP-9 (gelatinase-B) and MMP-10 (stromelysin-2). Conversely, IL-1 alpha reduced mRNA and protein expression of ADAMTS1, a metalloproteinase that suppresses neovascularization. IL-1 alpha increased expression of TIMP-1 slightly, but not TIMP-2. Data for MMP-1, MMP-2, MMP-3, MMP-9, MMP-10 and ADAMTS1 were confirmed by quantitative real-time RT-PCR. Tumor necrosis factor-alpha (TNF alpha), another important myocardial proinflammatory cytokine, did not alter expression of these metalloproteinases. IL-1 alpha strongly activated the p38 MAPK pathway in human CMF. Pharmacological inhibitors of p38-alpha/beta (SB203580) or p38-alpha/beta/gamma/delta (BIRB-0796) reduced MMP-3 and ADAMTS1 mRNA expression, but neither inhibitor affected MMP-9 levels. MMP-1 and MMP-10 expression were inhibited by BIRB-0796 but not SB203580, suggesting roles for p38-gamma/delta. In summary, IL-1 alpha induces a distinct pattern of ECM protein and protease expression in human CMF, in part regulated by distinct p38 MAPK subtypes, affirming the key role of IL-1 alpha and CMF in post-infarction cardiac remodeling. (C) 2010 Elsevier B.V. All rights reserved.
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