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01.11.2018 | Original Contribution | Ausgabe 6/2018 Open Access

Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress

Zeitschrift:: Basic Research in Cardiology > Ausgabe 6/2018

Autoren:: Andrey Kazakov, Rabea A. Hall, Christian Werner, Timo Meier, André Trouvain, Svetlana Rodionycheva, Alexander Nickel, Frank Lammert, Christoph Maack, Michael Böhm, Ulrich Laufs

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The online version of this article (https://doi.org/10.1007/s00395-018-0700-3) contains supplementary material, which is available to authorized users.

Abstract

Fibrosis is a hallmark of maladaptive cardiac remodelling. Here we report that genome-wide quantitative trait locus (QTL) analyses in recombinant inbred mouse lines of C57BL/6 J and DBA2/J strains identified Raf Kinase Inhibitor Protein (RKIP) as genetic marker of fibrosis progression. C57BL/6 N-RKIP^−/− mice demonstrated diminished fibrosis induced by transverse aortic constriction (TAC) or CCl₄ (carbon tetrachloride) treatment compared with wild-type controls. TAC-induced expression of collagen Iα2 mRNA, Ki67⁺ fibroblasts and marker of oxidative stress 8-hydroxyguanosine (8-dOHG)⁺ fibroblasts as well as the number of fibrocytes in the peripheral blood and bone marrow were markedly reduced in C57BL/6 N-RKIP^−/− mice. RKIP-deficient cardiac fibroblasts demonstrated decreased migration and fibronectin production. This was accompanied by a two-fold increase of the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), the main transcriptional activator of antioxidative proteins, and reduced expression of its inactivators. To test the importance of oxidative stress for this signaling, C57BL/6 J mice were studied. C57BL/6 J, but not the C57BL/6 N-strain, is protected from TAC-induced oxidative stress due to mutation of the nicotinamide nucleotide transhydrogenase gene (Nnt). After TAC surgery, the hearts of Nnt-deficient C57BL/6 J-RKIP^−/− mice revealed diminished oxidative stress, increased left ventricular (LV) fibrosis and collagen Iα2 as well as enhanced basal nuclear expression of Nrf2. In human LV myocardium from both non-failing and failing hearts, RKIP-protein correlated negatively with the nuclear accumulation of Nrf2. In summary, under conditions of Nnt-dependent enhanced myocardial oxidative stress induced by TAC, RKIP plays a maladaptive role for fibrotic myocardial remodeling by suppressing the Nrf2-related beneficial effects.

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Titel: Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress
Autoren:: Andrey Kazakov
Rabea A. Hall
Christian Werner
Timo Meier
André Trouvain
Svetlana Rodionycheva
Alexander Nickel
Frank Lammert
Christoph Maack
Michael Böhm
Ulrich Laufs
Publikationsdatum: 01.11.2018
DOI: https://doi.org/10.1007/s00395-018-0700-3
Verlag: Springer Berlin Heidelberg
Zeitschrift: Basic Research in Cardiology
Ausgabe 6/2018
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803

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Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress

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