title: Cardiac RKIP induces a beneficial β-adrenoceptor-dependent positive inotropy.
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.
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Schmid
authors.affiliation: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Berlin
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Tomasovic
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kahlert
authors.affiliation: Comprehensive Heart Failure Center, Würzburg, Germany.|Department of Internal Medicine I, University of Würzburg, Würzburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nordbeck
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Deiss
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Denzinger
authors.affiliation: Comprehensive Heart Failure Center, Würzburg, Germany.|Department of Internal Medicine I, University of Würzburg, Würzburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herrmann
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Weidendorfer
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Becker
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schäfer
authors.affiliation: Institute of Anatomy and Cell Biology, Würzburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wagner
authors.affiliation: Institute of Anatomy and Cell Biology, Würzburg, Germany.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Schmitt
authors.affiliation: Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.|German Centre for Cardiovascular Research, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Comprehensive Heart Failure Center, Würzburg, Germany.|Department of Internal Medicine I, University of Würzburg, Würzburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Weidemann
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.affiliation: Clinic for Internal Medicine III, Saarland University Hospital, Homburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Freiburg, Germany.|Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.affiliation: Comprehensive Heart Failure Center, Würzburg, Germany.|Department of Internal Medicine I, University of Würzburg, Würzburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.affiliation: Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.|German Centre for Cardiovascular Research, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Oliver J
authors.identifier: http://orcid.org/0000-0001-8223-2638
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.|Comprehensive Heart Failure Center, Würzburg, Germany.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.affiliation: Department of Pharmacology, Institute of Pharmacology and Toxicology, Würzburg, Germany.|Comprehensive Heart Failure Center, Würzburg, Germany.
authors.forename: Kristina
authors.identifier: http://orcid.org/0000-0002-5747-2207
authors.initials: K
authors.lastname: Lorenz
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D015180:Electrophoresis, Gel, Two-Dimensional; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics* / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C511482:PEBP1 protein, human; C550693:PEBP1 protein, rat; D049488:Phosphatidylethanolamine Binding Protein; C539308:Raf kinase inhibitory protein, mouse; D018342:Receptors, Adrenergic, beta-1