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: Evelyn Schmid, Stefan Neef, Christopher Berlin, Angela Tomasovic, Katrin Kahlert, Peter Nordbeck, Katharina Deiss, Sabrina Denzinger, Sebastian Herrmann, Erich Wettwer, Markus Weidendorfer, Daniel Becker, Florian Schäfer, Nicole Wagner, Süleyman Ergün, Joachim P Schmitt, Hugo A Katus, Frank Weidemann, Ursula Ravens, Christoph Maack, Lutz Hein, Georg Ertl, Oliver J Müller, Lars S Maier, Martin J Lohse, Kristina Lorenz
• Journal: Nature medicine (Nat Med) Vol. 21 Issue 11 Pg. 1298-306 (Nov 2015) ISSN: 1546-170X [Electronic] United States
• PMID: 26479924 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• PEBP1 protein, human
• PEBP1 protein, rat
• Phosphatidylethanolamine Binding Protein
• Raf kinase inhibitory protein, mouse
• Receptors, Adrenergic, beta-1

Topics

• Animals
• Chromatin Immunoprecipitation
• Electrophoresis, Gel, Two-Dimensional
• Gene Knock-In Techniques
• Gene Knockdown Techniques
• Gene Transfer Techniques
• Heart Failure (genetics, metabolism)
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Mice, Transgenic
• Myocardial Contraction (genetics)
• Myocytes, Cardiac (metabolism)
• Phosphatidylethanolamine Binding Protein (genetics, metabolism)
• Receptors, Adrenergic, beta-1 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction