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Cardiac RKIP induces a beneficial β-adrenoceptor–dependent positive inotropy

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An Erratum to this article was published on 04 February 2016

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Abstract

In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload–induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

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Figure 1: RKIP induces a well-tolerated type of chronically increased cardiac contractility.
Figure 2: RKIP protects mice from pressure overload–induced heart failure.
Figure 3: AAV9-RKIPWT–treated mice are protected from TAC-induced heart failure.
Figure 4: RKIP enhances β-adrenoceptor signaling.
Figure 5: β2AR protects RKIPWT mice from diastolic SR Ca2+ leakage.
Figure 6: RKIP induces positive inotropy but also protects from apoptosis and ectopic heartbeats.

Change history

  • 29 October 2015

    In the version of this article initially published, there are typographical errors in the labels to Fig. 3e–h: 'WT + AAV9-eGFP' and 'WT + AAV9-RKIPWT' are incorrect, and should be 'RKIP- + AAV9-eGFP' and 'RKIP- + AAV9-RKIPWT', respectively. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by Deutsche Forschungsgemeinschaft (DFG; Sonderforschungsbereich SFB688, TPA17 to K.L.) and by Bundesministerium für Bildung und Forschung (BMBF; Comprehensive Heart Failure Center Würzburg; project A2 to K.L., M.J.L. and F.W.). RKIP heterozygous knockout (Pebp1+/−) mice were kindly provided by the Mutant Mouse Regional Resource Center (MMRRC, a National Center for Research Resources and US National Institutes of Health–funded strain repository at the University of California, Davis; identification number 030379-UCD) and Adrb1−/− and Adrb2−/− mice by B. Kobilka (Department of Molecular and Cellular Physiology, Stanford University). We thank U. Zabel, A. Jungmann, R. Gilsbach, E. Schmitteckert, C. Hoffmann, S. Wagner and J. Bauer for valuable feedback and discussions and N. Yurdagül-Hemmrich, M. Babl, M. Fischer, T. Sowa, T. Schulte, L. Vlaskin, A.-K. Lamprecht and J. Becker for their excellent technical support.

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K.L., E.S., C.B., A.T., S.H., K.K., K.D., S.D., M.W., D.B., F.S., N.W. and S.E. performed experiments and analyzed data; S.N., E.W., J.P.S. and P.N. analyzed data; S.N., L.S.M., F.W., P.N., O.J.M., E.S., C.M., U.R., J.P.S., G.E., L.H. and H.A.K. provided feedback and revised the manuscript; K.L. and M.J.L. wrote the manuscript; K.L. designed the project.

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Correspondence to Martin J Lohse or Kristina Lorenz.

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Schmid, E., Neef, S., Berlin, C. et al. Cardiac RKIP induces a beneficial β-adrenoceptor–dependent positive inotropy. Nat Med 21, 1298–1306 (2015). https://doi.org/10.1038/nm.3972

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