Abstract 15516: Secretoneurin is a Novel Endogenous CaMKIId Inhibitor That Regulates Cardiomyocyte Calcium Handling and is Closely Associated With Mortality in Patients With Acute Heart Failure
Aims: To explore secretoneurin (SN), a functional fragment of secretogranin II that is increased in heart failure (HF), as a HF biomarker and possible regulator of cardiomyocyte Ca2+ homeostasis.
Methods and Results: SN was identified in the circulation of HF patients by liquid chromatography-mass spectrometry. Measuring SN levels on admission for acute HF in 143 patients, SN provided strong and independent information regarding mortality (n=66) during follow-up (median 776 days): hazard ratio [logSN] 4.27 (95% CI 1.83-9.94), p=0.001 in multivariate analysis. SN also reclassified patients to their correct risk strata on top of other predictors of mortality as assessed by the net reclassification index. We explored a role for SN in cardiomyocyte Ca2+ handling in experimental models. First, we found SN to be internalized into cardiomyocytes by endocytosis and to reduce Ca2+/calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ) activity via direct SN-CaM and SN-CaMKIIδ binding. SN also reduced CaMKIIδ-dependent phosphorylation of the ryanodine receptor, attenuated sarcoplasmic reticulum (SR) Ca2+ leak, and increased the magnitude and kinetics of cardiomyocyte Ca2+ transients and contractions via augmented SR Ca2+ content. Furthermore, SN reduced L-type Ca2+ current (ICaL), and the occurrence of arrhytmogenic Ca2+ waves.
Conclusions: We have identified SN as a novel, endogenous CaMKIIδ inhibitor that improves Ca2+ handling in cardiomyocyte. Since circulating SN levels are closely associated with mortality in HF patients, we believe SN production may be a compensatory mechanism that counteracts HF-induced alterations in cardiomyocyte Ca2+ handling in the most severely ill HF patients.
- © 2013 by American Heart Association, Inc.