Document Type

Article

Publication Date

9-17-2004

Description

Matrix metalloproteinases (MMPs), a family of endoproteinases, are implicated in cardiac remodeling. Interleukin-1β (IL-1β), which is increased in the heart following myocardial infarction, increases expression and activity of MMP-2 (gelatinase A) and -9 (gelatinase B) in cardiac fibroblasts. Previously, we have shown that IL-1β activates ERK1/2, JNKs, and protein kinase C (PKC). However, signaling pathways involved in the regulation of MMP-2 and -9 expression and activity are not yet well understood. Using adult rat cardiac fibroblasts, we show that inhibition of ERK1/2 and JNKs inhibits IL-1β-stimulated increases in MMP-9, not MMP-2, expression and activity. Chelerythrine, an inhibitor of PKC, inhibited activation of ERK1/2 and JNKs and expression and activity of both MMPs. Selective inhibition of PKC-α/β1 using Gö6976 inhibited JNKs activation and the expression and activity of MMP-9, not MMP-2. Inhibition of PKC-θ and PKC-ζ using pseudosubstrates inhibited IL-1β-stimulated activation of ERK1/2 and JNKs and the expression and activity of MMP-2 and -9. Inhibition of PKC-ε had no effect. IL-1β activated NF-κB pathway as measured by increased phosphorylation of IKKα/β and Inhibition of ERK1/2, JNKs, and PKC-α/β1 had no effect on NF-κB activation, whereas inhibition of PKC-θ and PKC-ζ inhibited IL-1β-stimulated activation of NF-κB. SN50, NF-κB inhibitor peptide, inhibited IL-1β-stimulated increases in MMP-2 and -9 expression and activity. These observations suggest that 1) activation of ERK1/2 and JNKs plays a critical role in the regulation of MMP-9, not MMP-2, expression and activity; 2) PKC-α/β1 act upstream of JNKs, not ERK1/2; 3) PKC-ζ and -θ, not PKC-ε, act upstream of JNKs, ERK1/2, and NF-κB; and 4) activation of NF-κB stimulates expression and activity of MMP-2 and -9.

Copyright Statement

© 2004 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.

Creative Commons Attribution (CC BY 4.0)

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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