Abstract 11793: Secretoneurin, a Peptide Associated with Mortality in Heart Failure, Modulates Cardiomyocyte Calcium Homeostasis
Background: In patients hospitalized with acute heart failure (HF), we have found a close association between plasma secretoneurin (SN) levels and the severity of HF, including a graded increase in mortality during follow-up according to admission SN level. We have recently also identified the cardiomyocytes of the left ventricle as important contributors to the elevated SN levels in HF, but currently no information is available about the influence of high SN levels on the pathophysiology of HF.
Aim: To assess the functional aspects of elevated SN levels in HF.
Methods: Functional aspects of SN were assessed in isolated cardiomyocytes and fibroblasts by immunoblotting, real-time PCR, confocal microscopy, and electrophysiology.
Results: SN perfusion (10 µg/mL) increased cardiomyocyte contraction by 53% vs. cells in standard buffer (p=0.01) and reduced the time to peak by 16% (p=0.01). SN stimulation also increased Ca2+ transient amplitude by 21% (p=0.002) and reduced the time to half decay by 14% (p=0.02). We observed a 21% increase in sarcoplasmic reticulum Ca2+ content (p<0.001) after SN stimulation, and a reduction in Ca2+ spark magnitude by 4% (p=0.05) with a corresponding reduction in width (12%, p<0.001) and duration (16%, p<0.001) of Ca2+ sparks. We observed that endogenous SN is distributed throughout the cytoplasm of cardiomyocytes, and found that AlexaFluor-labeled SN was taken up from the suspension to cardiomyocytes. No co-localization was observed with the non-specific uptake of dextran, indicating a distinct uptake mechanism for SN. Uptake of SN was verified by immunoblotting, where we found increased intracellular SN levels with higher concentration of SN applied to the cell culture. There was no effect of SN on cardiomyocyte hypertrophy or fibroblast function, as assessed by transcriptional alterations in genes involved in these processes.
Conclusion: We have found a direct effect of SN on cardiomyocyte Ca2+ homeostasis and specific uptake of SN in cardiomyocytes. The effect of SN on Ca2+ homeostasis could be clinically important as patients with HF and elevated SN levels have a poor prognosis.
- © 2011 by American Heart Association, Inc.