Downregulation of Matrix Metalloproteinases and Collagens and Suppression of Cardiac Fibrosis by Inhibition of the Proteasome

Abstract

Abstract-Myocardial remodeling is an adaptive response of the myocardium to several forms of stress culminating in cardiac fibrosis, left ventricular dilation, and loss of contractility. The remodeling processes of the extracellular matrix are controlled by matrix metalloproteinases, which are in turn regulated by growth factors and inflammatory cytokines. The inflammatory transcription factor nuclear factor B has been implicated in the transcriptional regulation of several matrix metalloproteinases. Because activation of nuclear factor B in turn is essentially controlled by the ubiquitinproteasome system, we investigated the hypothesis that inhibition of the proteasome may prevent activation of matrix metalloproteinases. We demonstrate here that inhibition of the proteasome in rat cardiac fibroblasts suppressed not only expression of matrix metalloproteinases 2 and 9, but also expression of collagen I␣1, I␣2, and III␣1 as determined by in-gel zymography and real-time reverse transcription-polymerase chain reaction. Moreover, myocardial expression of matrix metalloproteinases and collagens was effectively suppressed by systemic treatment of spontaneously hypertensive rats over 12 weeks with the proteasome inhibitor MG132, which resulted in a marked reduction of cardiac fibrosis (Ϫ38%) compared with control animals. We conclude that inhibition of the ubiquitin-proteasome system may provide a new and attractive tool to interfere with collagen and matrix metalloproteinase expression, and therefore might be of possible use in the therapy of myocardial remodeling.

Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts

“…Activation of MMP-2 and 9 by IL-1β is consistent with previous reports in cardiac fibroblasts. [16][17][18] Additionally, our data directly demonstrate increased MMP-3 expression and activity, extending a previous observation of IL-1β induced increase in MMP-3 mRNA. [17] In contrast to that study, we observe no evidence for IL-1β activation of MMP-13.…”

Autophagy Promotes Intracellular Degradation of Type I Collagen Induced by Transforming Growth Factor (TGF)-β1

“…In contrast to bafilomycin A 1 , we observed that the inhibition of the proteasome by treatment with MG132 repressed the expression of Col-I ␣1 mRNA in MMC. Similar effect of MG132 has been previously reported in human dermal fibroblasts (43) and rat cardiac fibroblasts (44).…”

“…This negative regulatory effect of MG132, in fact, has been previously shown in human dermal fibroblasts (43) and rat cardiac fibroblasts (44). However the precise mechanism by which proteasome inhibitor MG132 represses Col-I ␣1 mRNA expression remains to be determined.…”

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

“…It has been reported that [19] in experimental inflammatory bo wel disease MG-132 in vivo reduced T cell-mediated intestinal inflammation but significantly suppressed cell migration and epithelial cell proliferation. MG-132 also has an influence on the cardiovascular system [8,29,34]. In a low dose (0.1 mg/kg) MG-132 administered intraperitoneally once per day even for 2 or 8 weeks may effectively prevent cardiac remodelling and dysfunction in pressure-overloaded hearts without marked drug toxicity [29].…”