Abstract
BackgroundSeveral beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology.Methodology/Principal FindingsSgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p<0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-β and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age- and gender-matched control subjects: median 0.16 (Q1–3 0.14–0.18) vs. 0.12 (0.10–0.14) nmol/L, p<0.001.ConclusionsWe demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker.
Highlights
Heart failure (HF) is associated with changes in systemic and pulmonary hemodynamics, complex neurohumoral activation, as well as local molecular alterations in the myocardium [1]
We demonstrate increased myocardial secretogranin II (SgII) production and processing in the left ventricle (LV) in animals with myocardial infarction and heart failure (HF), which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis
Circulating SgII levels are increased in patients with chronic, stable HF and may represent a new cardiac biomarker
Summary
Heart failure (HF) is associated with changes in systemic and pulmonary hemodynamics, complex neurohumoral activation, as well as local molecular alterations in the myocardium [1]. Regulation of hormonal factors in the failing myocardium can directly affect function and survival of cardiac cells [1], and result in increased circulating levels of proteins secreted from the myocardium [2]. By identifying proteins that are regulated in the failing myocardium, we may enhance our understanding of the pathophysiology of HF and discover new diagnostic and prognostic HF biomarkers. The protein secretogranin II (SgII) is a 587 amino acid long protein from the chromogranin-secretogranin (granin) protein family [3]. Two other members of the granin protein family, chromogranin (Cg) A and B have been found increased in HF [4–. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
