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(Hypertension. 2004;44:471.)
© 2004 American Heart Association, Inc.

Scientific Contributions

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

Silke Meiners; Berthold Hocher; Andrea Weller; Michael Laule; Verena Stangl; Christoph Guenther; Michael Godes; Alexander Mrozikiewicz; Gert Baumann; Karl Stangl

From Medizinische Klinik (S.M., A.W., M.L., V.S., C.G., G.B., K.S.), Kardiologie and Center for Cardiovascular Research and Medizinische Klinik (B.H., M.G.), Nephrologie, Berlin, Germany; Institute of Clinical Pharmacology (A.M.), University Poznan, Poland.

Correspondence to Karl Stangl, MD, Medizinische Klinik, Charité, Schumannstrasse 20/21, D-10117 Berlin, Germany. E-mail karl.stangl{at}charite.de

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 ubiquitin-proteasome 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 I1, I2, and III1 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 (–38%) 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.

Key Words: myocardial remodeling • collagen • fibrosis

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