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Open Access 01-11-2018 | Original Contribution

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

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

Published in: Basic Research in Cardiology | Issue 6/2018

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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Ali SR, Ranjbarvaziri S, Talkhabi M, Zhao P, Subat A, Hojjat A, Kamran P, Müller AM, Volz KS, Tang Z, Red-Horse K, Ardehali R (2014) Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ Res 115:625–635. https://doi.org/10.1161/CIRCRESAHA.115.303794 CrossRefPubMed

Al-Mulla F, Bitar MS, Feng J, Park S, Yeung KC (2012) A new model for Raf kinase inhibitory protein induced chemotherapeutic resistance. PLoS One 7:e29532. https://doi.org/10.1371/journal.pone.0029532 CrossRefPubMedPubMedCentral

Al-Mulla F, Bitar MS, Taqi Z, Yeung KC (2013) RKIP: much more than Raf kinase inhibitory protein. J Cell Physiol 228:1688–1702. https://doi.org/10.1002/jcp.24335 CrossRefPubMed

Brown DI, Griendling KK (2015) Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res 116:531–549. https://doi.org/10.1161/CIRCRESAHA.116.303584 CrossRefPubMedPubMedCentral

Bubb KJ, Kok C, Tang O, Rasko NB, Birgisdottir AB, Hansen T, Ritchie R, Bhindi R, Reisman SA, Meyer C, Ward K, Karimi Galougahi K, Figtree GA (2017) The Nrf2 activator DH404 attenuates adverse ventricular remodeling post-myocardial infarction by modifying redox signalling. Free Radic Biol Med 108:585–594. https://doi.org/10.1016/j.freeradbiomed.2017.04.027 CrossRefPubMed

Cazanave SC, Sanyal AJ (2014) KEAP the balance between life and death. Mol Cell Oncol 2:e968065. https://doi.org/10.4161/23723548.2014.968065 CrossRefPubMedPubMedCentral

Czibik G, Derumeaux G, Sawaki D, Valen G, Motterlini R (2014) Heme oxygenase-1: an emerging therapeutic target to curb cardiac pathology. Basic Res Cardiol 109:450. https://doi.org/10.1007/s00395-014-0450-9 CrossRefPubMed

Di Minno A, Turnu L, Porro B, Squellerio I, Cavalca V, Tremoli E, Di Minno MND (2016) 8-hydroxy-2-deoxyguanosine levels and cardiovascular disease: a systematic review and meta-analysis of the literature. Antioxid Redox Signal 24:548–555. https://doi.org/10.1089/ars.2015.6508 CrossRefPubMedPubMedCentral

Erkens R, Kramer CM, Lückstädt W, Pankin C, Krause L, Weidenbach M, Dirzka J, Krenz T, Mergia E, Suvorava T, Kelm M, Cortese-Krott MM (2015) Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med 89:906–917. https://doi.org/10.4161/23723548.2014 CrossRefPubMed

10.

Fan X, Gu X, Zhao R, Zheng Q, Li L, Yang W, Ding L, Xue F, Fan J, Gong Y, Wang Y (2016) Cardiac β2-adrenergic receptor phosphorylation at ser 355/356 regulates receptor internalization and functional resensitization. PLoS One 11:e0161373. https://doi.org/10.1371/journal.pone.0161373 CrossRefPubMedPubMedCentral

11.

Fu X, Koller S, Abd Alla J, Quitterer U (2013) Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth-promoting mitogen-activated protein kinase (MAPK) pathway. J Biol Chem 288:7738–7755. https://doi.org/10.1074/jbc.M112.428078 CrossRefPubMedPubMedCentral

12.

Fujiu K, Nagai R (2013) Contributions of cardiomyocyte-cardiac fibroblast-immune cell interactions in heart failure development. Basic Res Cardiol 108:357. https://doi.org/10.1007/s00395-013-0357-x CrossRefPubMed

13.

Hall RA, Liebe R, Hochrath K, Kazakov A, Alberts R, Laufs U, Böhm M, Fischer HP, Williams RW, Schughart K, Weber SN, Lammert F (2014) Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population. PLoS One 9:e89279. https://doi.org/10.1371/journal.pone.0089279 CrossRefPubMedPubMedCentral

14.

Harris IS, Zhang S, Treskov I, Kovacs A, Weinheimer C, Muslin AJ (2004) Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation 110:718–723. https://doi.org/10.1161/01.CIR.0000138190.50127.6A CrossRefPubMed

15.

Itoh K, Wakabayashi N, Katoh Y, Ishii T, O´Connor T, Yamamoto M (2003) Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8:379–391. https://doi.org/10.1046/j.1365-2443.2003.00640.x CrossRefPubMed

16.

Jackson EK, Zhang Y, Gillespie DD, Zhu X, Cheng D, Jackson TC (2017) SDF-1α induces cardiac fibroblasts, renal microvascular smooth muscle cells and glomerular mesangial cells to proliferate, cause hypertrophy, and produce collagen. J Am Heart Assoc 6:e007253. https://doi.org/10.1161/JAHA.117.007253 CrossRefPubMedPubMedCentral

17.

Kazakov A, Hall R, Jagoda P, Bachelier K, Müller-Best P, Semenov A, Lammert F, Böhm M, Laufs U (2013) Inhibition of endothelial nitric oxide synthase induces and enhances myocardial fibrosis. Cardiovasc Res 100:211–221. https://doi.org/10.1093/cvr/cvt181 CrossRefPubMed

18.

Kazakov A, Meier T, Werner C, Hall R, Klemmer B, Körbel C, Lammert F, Maack C, Böhm M, Laufs U (2015) C-kit(+) resident cardiac stem cells improve left ventricular fibrosis in pressure overload. Stem Cell Res 15:700–711. https://doi.org/10.1016/j.scr.2015.10.017 CrossRefPubMed

19.

Keeley EC, Schutt RC, Marinescu MA, Burdick MD, Strieter RM, Mehrad B (2016) Circulating fibrocytes as predictors of adverse events in unstable angina. Transl Res 172(73–83):e1. https://doi.org/10.1016/j.trsl.2016.02.13 CrossRef

20.

Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, Shen J, Chen CT, Huo L, Hsu MC, Li CW, Ding Q, Liao TL, Lai CC, Lin AC, Chang YH, Tsai SF, Li LY, Hung MC (2009) KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell 36:131–140. https://doi.org/10.1016/j.molcel.2009.07.025 CrossRefPubMedPubMedCentral

21.

Lee DS, Gona P, Vasan RS, Larson MG, Benjamin EJ, Wang TJ, Tu JV, Levy D (2009) Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham heart study of the national heart, lung and blood institute. Circulation 119:3070–3077. https://doi.org/10.1161/CIRCULATIONAHA.108.815944 CrossRefPubMedPubMedCentral

22.

Lee SJ, Lee SH, Yoon MH, Park BJ (2013) A new p53 target gene, RKIP, is essential for DNA damage-induced cellular senescence and suppression of ERK activation. Neoplasia 15:727–737. https://doi.org/10.1593/neo.121862 CrossRefPubMedPubMedCentral

23.

Li J, Ichikawa T, Villacorta L, Janicki JS, Brower GL, Yamamoto M, Cui T (2009) Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol 29:1843–1850. https://doi.org/10.1161/ATVBAHA.109.189480 CrossRefPubMed

24.

Li XM, Ma YT, Yang YN, Liu F, Chen BD, Han W, Zhang JF, Gao XM (2009) Downregulation of survival signaling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure. Clin Exp Pharmacol Physiol 36:1054–1061. https://doi.org/10.1111/j.1440-1681.2009.05243.x CrossRefPubMed

25.

Li Y, Tang XH, Li XH, Dai HJ, Miao RJ, Cai JJ, Huang ZJ, Chen AF, Xing XW, Lu Y, Yuan H (2016) Regulator of G protein signalling 14 attenuates cardiac remodelling through the MEK-ERK1/2 signalling pathway. Basic Res Cardiol 111:47. https://doi.org/10.1007/s00395-016-0566-1 CrossRefPubMedPubMedCentral

26.

Liu L, Jin X, Hu CF, Zhang YP, Zhou Z, Li R, Shen CX (2018) Amphiregulin enhances cardiac fibrosis and aggravates cardiac dysfunction in mice with experimental myocardial infarction partly through activating EGFR-dependent pathway. Basic Res Cardiol 113:12. https://doi.org/10.1007/s00395-018-0669-y CrossRefPubMed

27.

Moore-Morris T, Guimarães-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, Gomez-Amaro R, Zhou B, Brenner DA, Peterson KL, Chen J, Evans SM (2014) Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest 124:2921–2934. https://doi.org/10.1172/JCI74783 CrossRefPubMedPubMedCentral

28.

Münzel T, Gori T, Keaney JF Jr, Maack C, Daiber A (2015) Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications. Eur Heart J 36:2555–2564. https://doi.org/10.1093/eurheartj/ehv305 CrossRefPubMed

29.

Nickel AG, von Hardenberg A, Hohl M, Löffler JR, Kohlhaas M, Becker J, Reil JC, Kazakov A, Bonnekoh J, Stadelmaier M, Puhl SL, Wagner M, Bogeski I, Cortassa S, Kappl R, Pasieka B, Lafontaine M, Lancaster CRD, Blacker TS, Hall AR, Duchen MR, Kästner L, Lipp P, Zeller T, Müller C, Knopp A, Laufs U, Böhm M, Hoth M, Maack C (2015) Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab 22:472–484. https://doi.org/10.1016/j.cmet.2015.07.008 CrossRefPubMed

30.

Nguyen T, Sherratt PJ, Huang H-C, Yang CS, Pickett CB (2003) Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. J Biol Chem 278:4536–4541. https://doi.org/10.1074/jbc.M207293200 CrossRefPubMed

31.

Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295. https://doi.org/10.1074/jbc.R900010200 CrossRefPubMedPubMedCentral

32.

Nikitaki Z, Hellweg CE, Georgakilas AG, Ravanat J-L (2015) Stress-induced DNA damage biomarkers: applications and limitations. Front Chem 3:35. https://doi.org/10.3389/fchem.2015.00035 CrossRefPubMedPubMedCentral

33.

Niture SK, Khatri R, Jaiswal AK (2014) Regulation of Nrf2-an update. Free Radic Biol Med 66:36–44. https://doi.org/10.1016/j.freeradbiomed.2013.02.008 CrossRefPubMed

34.

Oppermann M, Freedman NJ, Alexander RW, Lefkowitz RJ (1996) Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C. J Biol Chem 22:13266–13272. https://doi.org/10.1074/jbc.271.22.13266 CrossRef

35.

Pitcher JA, Tesmer JJ, Freeman JL, Capel WD, Stone WC, Lefkowitz RJ (1999) Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases. J Biol Chem 274:34531–34534. https://doi.org/10.1074/jbc.274.49.34531 CrossRefPubMed

36.

Qin Q, Qu C, Niu T, Zang H, Qi L, Lyu L, Wang X, Nagarkatti M, Nagarkatti P, Janicki JS, Wang XL, Cui T (2016) Nrf2-mediated cardiac maladaptive remodeling and dysfunction in a setting of autophagy insufficiency. Hypertension 67:107–117. https://doi.org/10.1161/HYPERTENSIONAHA.115.06062 CrossRefPubMed

37.

Sayeski PP, Ali MS, Safavi A, Lyles M, Kim SO, Frank SJ, Bernstein KE (1999) A catalytically active Jak2 is required for the angiotensin II-dependent activation of Fyn. J Biol Chem 274:33131–33142. https://doi.org/10.1074/jbc.274.46.33131 CrossRefPubMed

38.

Schmid E, Neef S, Berlin C, Tomasovic A, Kahlert K, Nordbeck P, Deiss K, Denzinger S, Herrmann S, Wettwer E, Weidendorfer M, Becker D, Schäfer F, Wagner N, Ergün S, Schmitt JP, Katus HA, Weidemann F, Ravens U, Maack C, Hein L, Ertl G, Müller OJ, Maier LS, Lohse MJ, Lorenz K (2015) Cardiac RKIP induces a beneficial β-adrenoceptor-dependent positive inotropy. Nat Med 21:1298–1306. https://doi.org/10.1038/nm.3972 CrossRefPubMed

39.

Strom J, Chen QM (2017) Loss of Nrf2 promotes rapid progression to heart failure following myocardial infarction. Toxicol Appl Pharmacol 327:52–58. https://doi.org/10.1016/j.taap.2017.03.025 CrossRefPubMed

40.

Talan MI, Ahmet I, Xiao R-P, Lakatta EG (2011) β2-AR agonists in treatment of chronic heart failure: long path to translation. J Mol Cell Cardiol 51:529–533. https://doi.org/10.1016/j.yjmcc.2010.09.019 CrossRefPubMed

41.

Theroux S, Pereira M, Casten KS, Burwell RD, Yeung KC, Sedivy JM, Klysik J (2007) Raf kinase inhibitory protein knockout mice: expression in the brain and olfaction deficit. Brain Res Bull 71:559–567. https://doi.org/10.1016/j.brainresbull.2006.11.010 CrossRefPubMed

42.

Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC (2016) Cardiac fibrosis: the fibroblast awakens. Circ Res 118:1021–1040. https://doi.org/10.1161/CIRCRESAHA.115.306565 CrossRefPubMedPubMedCentral

43.

Trial J, Heredia CP, Taffet GE, Entman ML, Cieslik KA (2017) Dissecting the role of myeloid and mesenchymal fibroblasts in age-dependent cardiac fibrosis. Basic Res Cardiol 112:34. https://doi.org/10.1007/s00395-017-0623-4 CrossRefPubMedPubMedCentral

44.

Xue M, Mormiji H, Rabbani N, Barker G, Bretschneider T, Shmygol A, Rand DA, Thornalley PJ (2015) Frequency modulated translocational oscillations of Nrf2 mediate the antioxidant response element cytoprotective transcriptional response. Antioxid Redox Signal 23:613–629. https://doi.org/10.1089/ars.2014.5962 CrossRefPubMedPubMedCentral

45.

Zhou S, Sun W, Zhang Z, Zheng Y (2014) The role of Nrf2-mediated pathway in cardiac remodeling and heart failure. Oxid Med Cell Longev 20:260429. https://doi.org/10.1155/2014/260429 CrossRef

46.

Zuern CS, Walker B, Sauter M, Schaub M, Chatterjee M, Mueller K, Rath D, Vogel S, Tegtmeyer R, Seizer P, Geisler T, Kandolf R, Lang F, Klingel K, Gawaz M, Borst O (2015) Endomyocardial expression of SDF-1 predicts mortality in patients with suspected myocarditis. Clin Res Cardiol 104:1033–1043. https://doi.org/10.1007/s00392-015-0871-y CrossRefPubMed

Title: Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress
Authors: Andrey Kazakov
Rabea A. Hall
Christian Werner
Timo Meier
André Trouvain
Svetlana Rodionycheva
Alexander Nickel
Frank Lammert
Christoph Maack
Michael Böhm
Ulrich Laufs
Publication date: 01-11-2018
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 6/2018
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-018-0700-3

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