Journal Article

Secretogranin II; a Protein Increased in the Myocardium and Circulation in Heart Failure with Cardioprotective Properties

Røsjø, Helge, Stensløkken, Kåre-Olav, Øie, Erik, Ottesen, Anett Hellebø, Sjaastad, Ivar, Husberg, Cathrine, Omland, Torbjørn, Christensen, Geir, Dahl, Mai Britt, Stridsberg, Mats, Florholmen, Geir, Louch, William E.

2012

Overview

Several 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. SgII 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. We 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animal models / Animals / Apoptosis / Apoptosis - drug effects / Biology / Biomarkers / Bone morphogenetic proteins / Cardiology / Cardiomyocytes / Cardiovascular disease / Chemokines / Circulation / Clinical medicine / Cytokines / Failure / Female / Gene expression / Growth factors / Heart / Heart attack / Heart attacks / Heart diseases / Heart failure / Heart Failure - blood / Heart Failure - genetics / Heart Failure - metabolism / Heart Failure - pathology / Heart Ventricles - metabolism / Heart Ventricles - pathology / Hospitals / Humans / Injury prevention / Ischemia / Male / Medical research / Medicine / Mice / Middle Aged / mRNA / Musculoskeletal system / Myocardial infarction / Myocardial ischemia / Myocardium / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - drug effects / Neuropeptides - pharmacology / Neuropeptides - therapeutic use / Norepinephrine / Norepinephrine - metabolism / Organs / Patients / Peptides / Phosphorylation / Proteases / Proteins / Rats / Reperfusion / Reperfusion Injury - drug therapy / RNA / Rodents / Secretogranin II - blood / Secretogranin II - genetics / Secretogranin II - metabolism / Secretogranin II - pharmacology / Secretogranin II - therapeutic use / Stat3 protein / Transforming Growth Factor beta - metabolism / Transforming growth factor-b / Tumor necrosis factor-TNF / Tumors / Up-Regulation / Ventricle