Secretoneurin is an endogenous calcium/calmodulin-dependent protein kinase II inhibitor that attenuates Ca2+-dependent arrhythmia

- Ottesen, Anett H.; Carlson, Catherine R.; Lunde, Marianne; Hoff, Jon Erik; Godang, Kristin; Sjaastad, Ivar; Pettilä, Ville; Stridsberg, Mats; Lehnart, Stephan E.; Edwards, Andrew G.; Lunde, Ida G.; Omland, Torbjørn; Eken, Olav Søvik; Stokke, Mathis K.; Christensen, Geir; Røsjø, Helge; Louch, William E.; Sadredini, Mani; Myhre, Peder L.; Shen, Xin; Dalhus, Bjørn; Laver, Derek R.; Lunde, Per Kristian; Kurola, Jouni

Title
Secretoneurin is an endogenous calcium/calmodulin-dependent protein kinase II inhibitor that attenuates Ca2+-dependent arrhythmia
Creator
Ottesen, Anett H.; Carlson, Catherine R.; Lunde, Marianne; Hoff, Jon Erik; Godang, Kristin; Sjaastad, Ivar; Pettilä, Ville; Stridsberg, Mats; Lehnart, Stephan E.; Edwards, Andrew G.; Lunde, Ida G.; Omland, Torbjørn; Eken, Olav Søvik; Stokke, Mathis K.; Christensen, Geir; Røsjø, Helge; Louch, William E.; Sadredini, Mani; Myhre, Peder L.; Shen, Xin; Dalhus, Bjørn; Laver, Derek R.; Lunde, Per Kristian; Kurola, Jouni
Relation
Circulation: Arrhythmia and Electrophysiology Vol. 12, Issue 4, no. e007045
Publisher Link
http://dx.doi.org/10.1161/CIRCEP.118.007045
Publisher
Lippincott Williams & Wilkins
Resource Type
journal article
Date
2019
Description
Background: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia. Methods: Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia–induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9–induced overexpression. Interactions between SN and CaMKIIδ were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca2+ homeostasis examined by fluorescence (fluo-4) and patch-clamp recordings in isolated cardiomyocytes. Results: SN levels were elevated in patients with CPVT and following ventricular arrhythmia–induced cardiac arrest. In contrast to NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9–induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKIIδ. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts and inhibited CaMKIIδ-dependent RyR phosphorylation. In line with CaMKIIδ and RyR inhibition, SN treatment decreased Ca2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca2+ current. Conclusions: SN production is upregulated in conditions with cardiomyocyte Ca2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.
Subject
calcium; calmodulin; heart failure; secretoneurin; tachycardia
Identifier
http://hdl.handle.net/1959.13/1424613
Identifier
uon:38114
Identifier
ISSN:1941-3084
Rights
© 2019 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
Language
eng
Full Text
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