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

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 I?2 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 I?2 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.

SUBMITTER: Kazakov A

PROVIDER: S-EPMC6133069 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Kazakov Andrey A Hall Rabea A RA Werner Christian C Meier Timo T Trouvain André A Rodionycheva Svetlana S Nickel Alexander A Lammert Frank F Maack Christoph C Böhm Michael M Laufs Ulrich U

Basic research in cardiology 20180906 6

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<sup>-/-</sup> mice demonstrated diminished fibrosis induced by transverse aortic constriction (TAC) or CCl<sub>4</sub> (carbon tetrachloride) treatment compared with wild-type controls. TAC-induced ...[more]

PMID: 30191336

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Project description:Kinase-targeted therapies have the potential to improve the survival of patients with cancer. However, the cancer-specific spectrum of kinase alterations exhibits distinct functional properties and requires mutation-oriented drug treatments. Besides post-translational modifications and diverse intermolecular interactions of kinases, it is the distinct disease mutation which reshapes full-length kinase conformations, affecting their activity. Oncokinase mutation profiles differ between cancer types, as it was shown for BRAF in melanoma and non-small-cell lung cancers. Here, we present the target-oriented application of a kinase conformation (KinCon) reporter platform for live-cell measurements of autoinhibitory kinase activity states. The bioluminescence-based KinCon biosensor allows the tracking of conformation dynamics of full-length kinases in intact cells and real time. We show that the most frequent BRAF cancer mutations affect kinase conformations and thus the engagement and efficacy of V600E-specific BRAF inhibitors (BRAFi). We illustrate that the patient mutation harboring KinCon reporters display differences in the effectiveness of the three clinically approved BRAFi vemurafenib, encorafenib, and dabrafenib and the preclinical paradox breaker PLX8394. We confirmed KinCon-based drug efficacy predictions for BRAF mutations other than V600E in proliferation assays using patient-derived lung cancer cell lines and by analyzing downstream kinase signaling. The systematic implementation of such conformation reporters will allow to accelerate the decision process for the mutation-oriented RAF-kinase cancer therapy. Moreover, we illustrate that the presented kinase reporter concept can be extended to other kinases which harbor patient mutations. Overall, KinCon profiling provides additional mechanistic insights into full-length kinase functions by reporting protein-protein interaction (PPI)-dependent, mutation-specific, and drug-driven changes of kinase activity conformations.

Dataset Information

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

Publications

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

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