Matrix metalloproteinases (MMPs), a family of extracellular endopeptidases, are implicated in angiogenesis because of their ability to selectively degrade components of the extracellular matrix. Interleukin-1β (IL-1β), increased in the heart post-myocardial infarction (post-MI), plays a protective role in the pathophysiology of left ventricular (LV) remodeling following MI. Here we studied expression of various angiogenic genes affected by IL-1β in cardiac microvascular endothelial cells (CMECs) and investigated the signaling pathways involved in the regulation of MMP-2. cDNA array analysis of 96 angiogenesis-related genes indicated that IL-1β modulates the expression of numerous genes, notably increasing the expression of MMP-2, not MMP-9. RT-PCR and Western blot analyses confirmed increased expression of MMP-2 in response to IL-1β. Gelatin in-gel zymography and Biotrak activity assay demonstrated that IL-1β increases MMP-2 activity in the conditioned media. IL-1β activated ERK1/2, JNKs, and protein kinase C (PKC), specifically PKCα/β1, and inhibition of these cascades partially inhibited IL-1β-stimulated increases in MMP-2. Inhibition of PKCα/β1 failed to inhibit ERK1/2. However, concurrent inhibition of PKCα/β1 and ERK1/2 almost completely inhibited IL-1β-mediated increases in MMP-2 expression. Inhibition of p38 kinase and nuclear factor-κB (NF-κB) had no effect. Pretreatment with superoxide dismutase (SOD) mimetic, MnTMPyP, increased MMP-2 protein levels, whereas pretreatment with SOD and catalase mimetic, EUK134, partially inhibited IL-1β-stimulated increases in MMP-2 protein levels. Exogenous H2O2 significantly increased MMP-2 protein levels, whereas superoxide generation by xanthine/xanthine oxidase had no effect. This in vitro study suggests that IL-1β modulates expression and activity of MMP-2 in CMECs.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etsu-works-19133 |
| Date | 01 February 2007 |
| Creators | Mountain, Deidra J.H., Singh, Mahipal, Menon, Bindu, Singh, Krishna |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Source | ETSU Faculty Works |
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