Interleukin-1beta increases expression and activity of matrix metalloproteinase-2 in cardiac microvascular endothelial cells: role of PKCalpha/beta1 and MAPKs |
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Authors: | Mountain Deidra J H Singh Mahipal Menon Bindu Singh Krishna |
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Institution: | Dept. of Physiology, James H. Quillen College of Medicine, East Tennessee State Univ., PO Box 70576, Johnson City, TN 37614, USA. singhk@etsu.edu |
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Abstract: | 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-1 (IL-1 ), 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-1 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-1 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-1 . Gelatin in-gel zymography and Biotrak activity assay demonstrated that IL-1 increases MMP-2 activity in the conditioned media. IL-1 activated ERK1/2, JNKs, and protein kinase C (PKC), specifically PKC / 1, and inhibition of these cascades partially inhibited IL-1 -stimulated increases in MMP-2. Inhibition of PKC / 1 failed to inhibit ERK1/2. However, concurrent inhibition of PKC / 1 and ERK1/2 almost completely inhibited IL-1 -mediated increases in MMP-2 expression. Inhibition of p38 kinase and nuclear factor- B (NF- B) 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-1 -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-1 modulates expression and activity of MMP-2 in CMECs. MMP-2; protein kinase C; ERK1/2; JNK |
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