Glycosylated Chromogranin A in Heart Failure

Abstract

Background— Chromogranin A (CgA) levels have previously been found to predict mortality in heart failure (HF), but currently no information is available regarding CgA processing in HF and whether the CgA fragment catestatin (CST) may directly influence cardiomyocyte function. Methods and Results— CgA processing was characterized in postinfarction HF mice and in patients with acute HF, and the functional role of CST was explored in experimental models. Myocardial biopsies from HF, but not sham-operated mice, demonstrated high molecular weight CgA bands. Deglycosylation treatment attenuated high molecular weight bands, induced a mobility shift, and increased shorter CgA fragments. Adjusting for established risk indices and biomarkers, circulating CgA levels were found to be associated with mortality in patients with acute HF, but not in patients with acute exacerbation of chronic obstructive pulmonary disease. Low CgA-to-CST conversion was also associated with increased mortality in acute HF, thus, supporting functional relevance of impaired CgA processing in cardiovascular disease. CST was identified as a direct inhibitor of CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase IIδ) activity, and CST reduced CaMKIIδ-dependent phosphorylation of phospholamban and the ryanodine receptor 2. In line with CaMKIIδ inhibition, CST reduced Ca 2+ spark and wave frequency, reduced Ca 2+ spark dimensions, increased sarcoplasmic reticulum Ca 2+ content, and augmented the magnitude and kinetics of cardiomyocyte Ca 2+ transients and contractions. Conclusions— CgA-to-CST conversion in HF is impaired because of hyperglycosylation, which is associated with clinical outcomes in acute HF. The mechanism for increased mortality may be dysregulated cardiomyocyte Ca 2+ handling because of reduced CaMKIIδ inhibition.

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

“…Because the processing of CgA to CST is compromised in several diseases, 41‐43 we determined plasma CgA and CST levels in patients with Crohn's disease and with ulcerative colitis, both with active disease and in remission (Figure 1E,F). In line with previous findings, 34‐36 we found higher CgA levels in plasma of patients with active Crohn's disease but not in patients in remission.…”

“…Among the various proteolytic peptides, we hypothesized that CST could be acting to balance the impact of PST, another peptide fragment of CgA (Figure 9B). This hypothesis was guided by prior work 43 alluding to PST’s deleterious impact on the gut mucosa, causing macrophage infiltration and inflammation. To test the nature of contribution of PST and CST on the gut paracellular barrier function, we supplemented the CgA‐KO mice with either CST alone (2 µg/g body weight for 15 days), or PST alone (2 µg/g body weight for 15 days), or both PST and CST co‐administered at equimolar ratio for 15 days.…”

Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values

“…CgA was also proposed as an important biomarker in diabetes (Broedbaek and Hilsted, 2016). Recent studies evaluated CgA as a valuable biomarker in various stressful diseases including neuroendocrine tumors (Di Giacinto et al, 2018), cardiovascular disorders (Ottesen et al, 2017; Mahata et al, 2018), atopic dermatitis (Cai et al, 2018), ulcerative colitis (Magnusson et al, 2018) and diabetes mellitus (Herold et al, 2018).…”

Catestatin as a Target for Treatment of Inflammatory Diseases

“…These anti-insulin actions of PST are likely important in maintaining homeostasis in glucose metabolism ( 7 , 42 , 94 ). The exact regulation of the proteolytic generation of CST and PST remains to be elucidated, but it could be coupled to metabolism via glycosylation because hyper-glycosylation of CgA is known to lead to reduced levels of CST ( 117 ). Thereby, the generation of CgA cleavage products might be regulated by sugar levels and this might play a role in progression of metabolic diseases, as for instance the increased blood glucose levels in T2DM might promote glycosylation of CgA.…”