title: Downregulation of matrix metalloproteinases and collagens and suppression of cardiac fibrosis by inhibition of the proteasome.
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 kappaB has been implicated in the transcriptional regulation of several matrix metalloproteinases. Because activation of nuclear factor kappaB 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 Ialpha1, Ialpha2, and IIIalpha1 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.
authors.affiliation: Medizinische Klinik, Kardiologie and Center for Cardiovascular Research, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.forename: Andrea
authors.initials: A
authors.lastname: Weller
authors.forename: Michael
authors.initials: M
authors.lastname: Laule
authors.forename: Verena
authors.initials: V
authors.lastname: Stangl
authors.forename: Christoph
authors.initials: C
authors.lastname: Guenther
authors.forename: Michael
authors.initials: M
authors.lastname: Godes
authors.forename: Alexander
authors.initials: A
authors.lastname: Mrozikiewicz
authors.forename: Gert
authors.initials: G
authors.lastname: Baumann
authors.forename: Karl
authors.initials: K
authors.lastname: Stangl
mesh_terms: D000818:Animals; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D005347:Fibroblasts; D005355:Fibrosis; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D020257:Ventricular Remodeling
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D003094:Collagen; D020782:Matrix Metalloproteinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde