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- Ottesen, Anett Hellebø, et al.
(författare)
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Glycosylated Chromogranin A in Heart Failure : Implications for Processing and Cardiomyocyte Calcium Homeostasis
- 2017
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Ingår i: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 10:2
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Tidskriftsartikel (refereegranskat)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.
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- Ottesen, Anett Hellebø, et al.
(författare)
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Secretoneurin is a novel prognostic cardiovascular biomarker associated with cardiomyocyte calcium handling.
- 2015
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 65:4, s. 339-51
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information and influences cardiomyocyte function is unknown.OBJECTIVES: This study sought to evaluate the merit of SN as a cardiovascular biomarker and assess effects of SN on cardiomyocyte Ca(2+) handling.METHODS: We assessed the association between circulating SN levels and mortality in 2 patient cohorts and the functional properties of SN in experimental models.RESULTS: In 143 patients hospitalized for acute HF, SN levels were closely associated with mortality (n = 66) during follow-up (median 776 days; hazard ratio [lnSN]: 4.63; 95% confidence interval: 1.93 to 11.11; p = 0.001 in multivariate analysis). SN reclassified patients to their correct risk strata on top of other predictors of mortality. In 155 patients with ventricular arrhythmia-induced cardiac arrest, SN levels were also associated with short-term mortality (n = 51; hazard ratio [lnSN]: 3.33; 95% confidence interval: 1.83 to 6.05; p < 0.001 in multivariate analysis). Perfusing hearts with SN yielded markedly increased myocardial levels and SN internalized into cardiomyocytes by endocytosis. Intracellularly, SN reduced Ca(2+)/calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ) activity via direct SN-CaM and SN-CaMKII binding and attenuated CaMKIIδ-dependent phosphorylation of the ryanodine receptor. SN also reduced sarcoplasmic reticulum Ca(2+) leak, augmented sarcoplasmic reticulum Ca(2+) content, increased the magnitude and kinetics of cardiomyocyte Ca(2+) transients and contractions, and attenuated Ca(2+) sparks and waves in HF cardiomyocytes.CONCLUSIONS: SN provided incremental prognostic information to established risk indices in acute HF and ventricular arrhythmia-induced cardiac arrest.
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