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RECEPTORS AND SIGNAL TRANSDUCTION

Interleukin-1 increases expression and activity of matrix metalloproteinase-2 in cardiac microvascular endothelial cells: role of PKC/₁ and MAPKs

Department of Physiology, James H. Quillen College of Medicine, James H. Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee

Submitted 7 April 2006 ; accepted in final form 18 September 2006

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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