P556Secretoneurin is increased in the myocardium in heart failure and may influence pathophysiology by modulating cardiomyocyte calcium homeostasis

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To assess a role forsecretoneurin (SN), a peptide of the chromogranin-secretogranin family, in the pathophysiologyof heart failure (HF).


Production of SN wasexamined in a post-infarction HF mouse model,and functional aspects assessed in isolated cardiomyocytes and fibroblasts.


In animals characterized by echocardiography one week after myocardial infarction, pro-SN mRNA levels were 11.5 fold upregulatedin the left ventricle (LV) of HF animals compared to sham-operated animals(p < 0.001). SN protein levels were also higher in the LV of HF animals, andSN production was confined to cardiomyocytes. By immunoblotting we foundincreased processing of pro-SN to shorter SN fragments. The principal proteasesof pro-SN PC1/3 and PC2 were increased in the LV of HF animals (3.5 foldincrease vs. sham, p < 0.001). AlexaFluor-labeled SN wastaken up from the suspension to cardiomyocytes in vitro, and there was no co-localization with the non-specificuptake of dextran. SN uptake was also verified by immunoblotting. Perfusingcardiomyocytes with SN (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).Ca2+ transient amplitudewas increased by 21% (p=0.002) and the time to half decay reduced by 14% (p=0.02).SN stimulation reduced Ca2+ spark magnitude by 4% (p=0.05), width by 12%, and duration by 16% (p < 0.001for both). The sarcoplasmic reticulum (SR) Ca2+ content was increased by 21% in cells perfusedwith SN (p < 0.001), but we did not observe altered Ca2+ reuptake into the SR or extrusion from the cell. There was no effect of SN on cardiomyocyte hypertrophy or fibroblast function, as assessedby transcriptional alterations in genes involved in these processes.


We have identified SN as a peptide that is increased in HF and which may influenceHF pathophysiology by modulating cardiomyocyte Ca2+ homeostasis.

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