Abstract
We have shown that osteopontin (OPN), an extracellular matrix protein, plays an important role in post myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation. Interleukin-1beta (IL-1beta), increased in the heart following MI, increases matrix metalloproteinase (MMP) activity in cardiac fibroblasts in vitro. Here, we show that OPN alone has no effect on MMP activity or expression. However, it reduces IL-1beta-stimulated increases in MMP activity and expression in adult rat cardiac fibroblasts. Pretreatment with bovine serum albumin had no effect on MMP activity or protein content, whereas GRGDS (glycine-arginine-glycine-aspartic acid-serine)-pentapeptide (which interrupts binding of RGD-containing proteins to cell surface integrins) and monoclonal antibody m7E3 (a rat beta3 integrins antagonist) inhibited the effects of OPN. Inhibition of PKC using chelerythrine inhibited the activities of both MMP-2 and MMP-9. Stimulation of cells using IL-1beta increased phosphorylation and translocation of PKC to membrane fractions, which was inhibited by OPN. OPN inhibited IL-1beta-stimulated increases in translocation of PKC-zeta from cytosolic to membrane fractions. Furthermore, the levels of phospho-PKC-zeta were lower in the cytosolic fractions of OPN knock-out mice hearts as compared with wild type 6 days post-MI. Inhibition of PKC-zeta using PKC-zeta pseudosubstrate inhibited IL-1beta-stimulated increases in MMP-2 and MMP-9 activities. These observations suggest that OPN, acting via beta3 integrins, inhibits IL-1beta-stimulated increases in MMP-2 and MMP-9 activity, at least in part, via the involvement of PKC-zeta. Thus, OPN may play a key role in collagen deposition during myocardial remodeling following MI by modulating cytokine-stimulated MMP activity.
Highlights
From the ‡Department of Physiology, James H
Treatment of cells with OPN inhibited IL-1-stimulated matrix metalloproteinase (MMP)-2 and MMP-9 activities
We have shown that increased expression of OPN in the heart plays an important role in post-myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation [10]
Summary
Vol 278, No 49, Issue of December 5, pp. 48546 –48552, 2003 Printed in U.S.A. Osteopontin Inhibits Interleukin-1-stimulated Increases in Matrix Metalloproteinase Activity in Adult Rat Cardiac Fibroblasts. In cells of non-cardiac origin, activation of protein kinase C (PKC) is suggested to play a critical role in the IL-1, interleukin-1; PKC, protein kinase C; BSA, bovine serum albumin; KO, knock-out; WT, wild type; ANOVA, analysis of variance. Among the PKC isoforms, the activation of PKC- (atypical isoform) is shown to be essential for MMP-1, MMP-3, and MMP-9 secretion in rabbit smooth muscle cells [28] Since both OPN and IL-1 are increased during pathophysiological conditions of the heart, we hypothesized that OPN increases collagen accumulation in the heart following MI by inhibiting IL-1-stimulated MMP activity. The data presented here suggest that OPN inhibits IL-1-stimulated increases in MMP-2 and MMP-9 activity via the involvement of PKC-
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