Abstract
Background: Secretoneurin (SN) is a peptide belonging to the granin protein family. As two other granin proteins, chromogranin A and B, are increased in cardiac tissue in heart failure (HF), we hypothesized that SN could play a role in cardiovascular pathophysiology. Methods: Production and functional aspects of SN were assessed in experimental models and circulating levels measured in two cohorts of HF patients. Results: Pro-SN mRNA levels were 11.5 fold increased in viable left ventricular (LV) tissue of mice subjected to coronary artery ligation and with echocardiographical confirmed HF. Protein levels were also increased in the LV of HF animals vs. sham-operated animals, including in the ischemic border zone where we observed increased processing from pro-SN to shorter SN fragments (>100% increase, p=0.001). Immunohistochemistry localized myocardial SN production to cardiomyocytes. We did not observe increased SN production in other organs than the LV. Perfusing isolated cardiomyocytes with SN rapidly induced Stat3 and Erk1/2 phosphorylation, protected from hydrogen peroxide-induced cardiomyocyte apoptosis in vitro , and reduced ischemia-reperfusion injury by 30% (p<0.05) in the isolated perfused rat heart. Circulating levels of SN were increased in patients with stable and acute HF compared to control subjects and increased in proportion to HF severity as evaluated by NYHA functional class (p=0.04 for trend). In 68 patients hospitalized for acute HF, admission SN levels provided excellent discrimination for all-cause mortality (n=17) during a median follow-up of 373 days: Hazard ratio [per 0.05 nmol/L increase of SN] 2.34 (95% CI 1.63-3.38), p<0.001. Adjustment for established clinical risk factors including comorbidities, renal function, and LV ejection fraction in multivariate analysis did not attenuate the association between SN levels and mortality: HR 2.43 (95% CI 1.63-3.61), p<0.001. Conclusion: SN production is increased in viable cardiomyocytes adjacent to the infarcted area in animals with myocardial infarction and HF, which could be beneficial as SN protects from myocardial ischemia. Based on our results, SN could represent a protective feedback response that is activated in proportion to the severity of HF.
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