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Secretoneurin Is an Endogenous Calcium/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca2+-Dependent Arrhythmia
Akershus Univ Hosp, Div Med, Sykehusveien 25, N-1478 Lorenskog, Norway;Oslo Univ Hosp, Inst Expt Med Res, Oslo, Norway;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.
Oslo Univ Hosp, Inst Expt Med Res, Oslo, Norway;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.
Oslo Univ Hosp, Inst Expt Med Res, Oslo, Norway;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.
Oslo Univ Hosp, Inst Expt Med Res, Oslo, Norway;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.
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2019 (English)In: Circulation: Arrhythmia and Electrophysiology, ISSN 1941-3149, E-ISSN 1941-3084, Vol. 12, no 4, article id e007045Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKII delta (Ca2+/calmodulin-dependent protein kinase II delta) 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 CaMKII delta 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 patchclamp 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 proB- 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 CaMKII delta. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKII delta in Langendorff hearts and inhibited CaMKII delta-dependent RyR phosphorylation. In line with CaMKII delta 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.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2019. Vol. 12, no 4, article id e007045
Keywords [en]
calcium, calmodulin, heart failure, secretoneurin, tachycardia
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-387564DOI: 10.1161/CIRCEP.118.007045ISI: 000469355500005PubMedID: 30943765OAI: oai:DiVA.org:uu-387564DiVA, id: diva2:1330023
Funder
EU, Horizon 2020, 647714Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved

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