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Current Heart Failure Reports

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01-12-2017 | Pathophysiology: Neuroendocrine, Vascular, and Metabolic Factors (S Katz, Section Editor)

Glycosylated Chromogranin A: Potential Role in the Pathogenesis of Heart Failure

Authors: Anett H. Ottesen, Geir Christensen, Torbjørn Omland, Helge Røsjø

Published in: Current Heart Failure Reports | Issue 6/2017

Abstract

Purpose of Review

Endocrine and paracrine factors influence the cardiovascular system and the heart by a number of different mechanisms. The chromogranin-secretogranin (granin) proteins seem to represent a new family of proteins that exerts both direct and indirect effects on cardiac and vascular functions. The granin proteins are produced in multiple tissues, including cardiac cells, and circulating granin protein concentrations provide incremental prognostic information to established risk indices in patients with myocardial dysfunction. In this review, we provide recent data for the granin proteins in relation with cardiovascular disease, and with a special focus on chromogranin A and heart failure.

Recent Findings

Chromogranin A is the most studied member of the granin protein family, and shorter, functionally active peptide fragments of chromogranin A exert protective effects on myocardial cell death, ischemia-reperfusion injury, and cardiomyocyte Ca²⁺ handling. Granin peptides have also been found to induce angiogenesis and vasculogenesis. Protein glycosylation is an important post-translational regulatory mechanism, and we recently found chromogranin A molecules to be hyperglycosylated in the failing myocardium. Chromogranin A hyperglycosylation impaired processing of full-length chromogranin A molecules into physiologically active chromogranin A peptides, and patients with acute heart failure and low rate of chromogranin A processing had increased mortality compared to other acute heart failure patients. Other studies have also demonstrated that circulating granin protein concentrations increase in parallel with heart failure disease stage.

Summary

The granin protein family seems to influence heart failure pathophysiology, and chromogranin A hyperglycosylation could directly be implicated in heart failure disease progression.

Ponikowski P, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail, 2016. 2016;18(8):891–975.CrossRef

Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet. 2011;378(9792):704–12.PubMedPubMedCentralCrossRef

Omland T. Advances in congestive heart failure management in the intensive care unit: B-type natriuretic peptides in evaluation of acute heart failure. Crit Care Med. 2008;36(1 Suppl):S17–27.PubMedCrossRef

Semenov AG, et al. Processing of pro-brain natriuretic peptide is suppressed by O-glycosylation in the region close to the cleavage site. Clin Chem. 2009;55(3):489–98.PubMedCrossRef

Lunde IG, et al. Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure. Physiol Genomics. 2012;44(2):162–72.PubMedCrossRef

Sanada S, et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest. 2007;117(6):1538–49.PubMedPubMedCentralCrossRef

Kempf T, et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med. 2011;17(5):581–8.PubMedCrossRef

• Bartolomucci A, et al. The extended granin family: structure, function, and biomedical implications. Endocr Rev. 2011;32(6):755–97. Comprehensive review of the granin protein family PubMedPubMedCentralCrossRef

Huttner WB, Gerdes HH, Rosa P. The granin (chromogranin/secretogranin) family. Trends Biochem Sci. 1991;16(1):27–30.PubMedCrossRef

10.

Røsjø H, et al. Secretogranin II; a protein increased in the myocardium and circulation in heart failure with cardioprotective properties. PLoS One. 2012;7(5):e37401.PubMedPubMedCentralCrossRef

11.

Eskeland NL, et al. Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway. J Clin Invest. 1996;98(1):148–56.PubMedPubMedCentralCrossRef

12.

Biswas N, et al. Proteolytic cleavage of human chromogranin A containing naturally occurring catestatin variants: differential processing at catestatin region by plasmin. Endocrinology. 2008;149(2):749–57.PubMedCrossRef

13.

Jiang Q, et al. Proteolytic cleavage of chromogranin A (CgA) by plasmin. Selective liberation of a specific bioactive CgA fragment that regulates catecholamine release. J Biol Chem. 2001;276(27):25022–9.PubMedCrossRef

14.

Biswas N, et al. Cathepsin L colocalizes with chromogranin A in chromaffin vesicles to generate active peptides. Endocrinology. 2009;150(8):3547–57.PubMedPubMedCentralCrossRef

15.

Helle KB. Comparative studies on the soluble protein fractions of bovine, equine, porcine and ovine adrenal chromaffin granules. Biochem J. 1966;100(1):6C–7C.PubMedPubMedCentralCrossRef

16.

O'Connor DT. Chromogranin: widespread immunoreactivity in polypeptide hormone producing tissues and in serum. Regul Pept. 1983;6(3):263–80.PubMedCrossRef

17.

Taupenot L, Harper KL, O'Connor DT. The chromogranin-secretogranin family. N Engl J Med. 2003;348(12):1134–49.PubMedCrossRef

18.

Winkler H, Fischer-Colbrie R. The chromogranins A and B: the first 25 years and future perspectives. Neuroscience. 1992;49(3):497–528.PubMedCrossRef

19.

• Pieroni M, et al. Myocardial production of chromogranin A in human heart: a new regulatory peptide of cardiac function. Eur Heart J. 2007;28(9):1117–27. First study to demonstrate increased myocardial CgA production in heart failure PubMedCrossRef

20.

Biswas N, et al. Chromogranin/secretogranin proteins in murine heart: myocardial production of chromogranin A fragment catestatin (Chga(364–384)). Cell Tissue Res. 2010;342(3):353–61.PubMedPubMedCentralCrossRef

21.

Røsjø H, et al. Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial. Eur J Heart Fail. 2010;12(6):549–56.PubMedCrossRef

22.

Rosa P, et al. The major tyrosine-sulfated protein of the bovine anterior pituitary is a secretory protein present in gonadotrophs, thyrotrophs, mammotrophs, and corticotrophs. J Cell Biol. 1985;100(3):928–37.PubMedCrossRef

23.

Fischer-Colbrie R, Hagn C, Schober M. Chromogranins A, B, and C: widespread constituents of secretory vesicles. Ann N Y Acad Sci. 1987;493:120–34.PubMedCrossRef

24.

Heidrich FM, et al. Chromogranin B regulates calcium signaling, nuclear factor kappaB activity, and brain natriuretic peptide production in cardiomyocytes. Circ Res. 2008;102(10):1230–8.PubMedPubMedCentralCrossRef

25.

Bergh J, et al. The release of chromogranin A and B like activity from human lung cancer cell lines. A potential marker for a subset of small cell lung cancer. Acta Oncol. 1989;28(5):651–4.PubMedCrossRef

26.

Sobol RE, et al. Elevated serum chromogranin A concentrations in small-cell lung carcinoma. Ann Intern Med. 1986;105(5):698–700.PubMedCrossRef

27.

Angelsen A, et al. Neuroendocrine differentiation in carcinomas of the prostate: do neuroendocrine serum markers reflect immunohistochemical findings? Prostate. 1997;30(1):1–6.PubMedCrossRef

28.

Angelsen A, et al. Use of neuroendocrine serum markers in the follow-up of patients with cancer of the prostate. Prostate. 1997;31(2):110–7.PubMedCrossRef

29.

Paco S, et al. Regulation of exocytotic protein expression and Ca²⁺-dependent peptide secretion in astrocytes. J Neurochem. 2009;110(1):143–56.PubMedCrossRef

30.

Troger J, et al. Release of secretoneurin and noradrenaline from hypothalamic slices and its differential inhibition by calcium channel blockers. Naunyn Schmiedebergs Arch Pharmacol. 1994;349(6):565–9.PubMedCrossRef

31.

Mahata SK, et al. Neuroendocrine cell type-specific and inducible expression of chromogranin/secretogranin genes: crucial promoter motifs. Ann N Y Acad Sci. 2002;971:27–38.PubMedCrossRef

32.

Steiner HJ, et al. Chromogranins A and B are co-localized with atrial natriuretic peptides in secretory granules of rat heart. J Histochem Cytochem. 1990;38(6):845–50.PubMedCrossRef

33.

Yoo SH, et al. Coupling of the inositol 1,4,5-trisphosphate receptor and chromogranins A and B in secretory granules. J Biol Chem. 2000;275(17):12553–9.PubMedCrossRef

34.

Yoo SH. Secretory granules in inositol 1,4,5-trisphosphate-dependent Ca²⁺ signaling in the cytoplasm of neuroendocrine cells. FASEB J. 2010;24(3):653–64.PubMedPubMedCentralCrossRef

35.

Yoo SH, Huh YH, Hur YS. Inositol 1,4,5-trisphosphate receptor in chromaffin secretory granules and its relation to chromogranins. Cell Mol Neurobiol. 2010;30(8):1155–61.PubMedCrossRef

36.

Yoo SH, Hur YS. Enrichment of the inositol 1,4,5-trisphosphate receptor/Ca²⁺ channels in secretory granules and essential roles of chromogranins. Cell Calcium. 2012;51(3-4):342–50.PubMedCrossRef

37.

• Mahapatra NR, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest. 2005;115(7):1942–52. First study to demonstrate that CHGA-/- mice develop a heart failure phenotype PubMedPubMedCentralCrossRef

38.

Mahata SK, et al. Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist. J Clin Invest. 1997;100(6):1623–33.PubMedPubMedCentralCrossRef

39.

Angelone T, et al. The antihypertensive chromogranin a peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism. Endocrinology. 2008;149(10):4780–93.PubMedPubMedCentralCrossRef

40.

Theurl M, et al. The neuropeptide catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. Circ Res. 2010;107(11):1326–35.PubMedCrossRef

41.

O'Connor DT, et al. Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension. J Hypertens. 2002;20(7):1335–45.PubMedCrossRef

42.

Rao F, et al. Catecholamine release-inhibitory peptide catestatin (chromogranin A(352–372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension. Circulation. 2007;115(17):2271–81.PubMedCrossRef

43.

O'Connor DT, et al. Pancreastatin: multiple actions on human intermediary metabolism in vivo, variation in disease, and naturally occurring functional genetic polymorphism. J Clin Endocrinol Metab. 2005;90(9):5414–25.PubMedCrossRef

44.

Fung MM, et al. Direct vasoactive effects of the chromogranin A (CHGA) peptide catestatin in humans in vivo. Clin Exp Hypertens. 2010;32(5):278–87.PubMedPubMedCentralCrossRef

45.

Egger M, et al. Monocyte migration: a novel effect and signaling pathways of catestatin. Eur J Pharmacol. 2008;598(1-3):104–11.PubMedCrossRef

46.

Zhang D, et al. Two chromogranin A-derived peptides induce calcium entry in human neutrophils by calmodulin-regulated calcium independent phospholipase A2. PLoS One. 2009;4(2):e4501.PubMedPubMedCentralCrossRef

47.

Aardal S, Helle KB. The vasoinhibitory activity of bovine chromogranin A fragment (vasostatin) and its independence of extracellular calcium in isolated segments of human blood vessels. Regul Pept. 1992;41(1):9–18.PubMedCrossRef

48.

• Ottesen AH, et al. Secretoneurin is a novel prognostic cardiovascular biomarker associated with cardiomyocyte calcium handling. J Am Coll Cardiol. 2015;65(4):339–51. First study to demonstrate a direct link between granin peptides and cardiomyocyte Ca2+ handling PubMedCrossRef

49.

Anderson ME, Brown JH, Bers DM. CaMKII in myocardial hypertrophy and heart failure. J Mol Cell Cardiol. 2011;51(4):468–73.PubMedPubMedCentralCrossRef

50.

Angelone T, et al. Phosphodiesterase type-2 and NO-dependent S-nitrosylation mediate the cardioinhibition of the antihypertensive catestatin. Am J Physiol Heart Circ Physiol. 2012;302(2):H431–42.PubMedCrossRef

51.

• Ottesen AH, et al. Glycosylated chromogranin A in heart failure: implications for processing and cardiomyocyte calcium homeostasis. Circ Heart Fail. 2017. 10(2). First study to report myocardial CgA hyperglycosylation in heart failure and that this may influence disease progression

52.

Rosjo H, et al. Chromogranin B in heart failure: a putative cardiac biomarker expressed in the failing myocardium. Circ Heart Fail. 2010;3(4):503–11.PubMedCrossRef

53.

• Ceconi C, et al. Chromogranin A in heart failure; a novel neurohumoral factor and a predictor for mortality. Eur Heart J. 2002;23(12):967–74. First study to demonstrate increased circulating CgA concentrations in parallel with heart failure severity and the potential of CgA as a cardiac biomarker PubMedCrossRef

54.

Omland T, Dickstein K, Syversen U. Association between plasma chromogranin A concentration and long-term mortality after myocardial infarction. Am J Med. 2003;114(1):25–30.PubMedCrossRef

55.

Estensen ME, et al. Prognostic value of plasma chromogranin A levels in patients with complicated myocardial infarction. Am Heart J. 2006;152(5):927. e1-6PubMedCrossRef

56.

Jansson AM, et al. Prognostic value of circulating chromogranin A levels in acute coronary syndromes. Eur Heart J. 2009;30(1):25–32.PubMedCrossRef

57.

Røsjø H, et al. Prognostic value of chromogranin A in severe sepsis: data from the FINNSEPSIS study. Intensive Care Med. 2012;38(5):820–9.PubMedCrossRef

58.

Zhang D, et al. Prognostic value of chromogranin A at admission in critically ill patients: a cohort study in a medical intensive care unit. Clin Chem. 2008;54(9):1497–503.PubMedCrossRef

59.

Lu L, et al. Reduced serum levels of vasostatin-2, an anti-inflammatory peptide derived from chromogranin A, are associated with the presence and severity of coronary artery disease. Eur Heart J. 2012;33(18):2297–306.PubMedCrossRef

60.

Zhu D, et al. Catestatin is useful in detecting patients with stage B heart failure. Biomarkers. 2011;16(8):691–7.PubMedCrossRef

61.

Goetze JP, et al. Making sense of chromogranin A in heart disease. Lancet Diabetes Endocrinol. 2013;1(1):7–8.PubMedCrossRef

62.

Myhre PL, et al. Circulating chromogranin B levels in patients with acute respiratory failure: data from the FINNALI Study. Biomarkers. 2017: 1–7.

63.

Leitner B, et al. Secretogranin II: relative amounts and processing to secretoneurin in various rat tissues. J Neurochem. 1996;66(3):1312–7.PubMedCrossRef

64.

Røsjø H, et al. Prognostic value of secretoneurin in critically ill patients with infections. Crit Care Med. 2016;44(10):1882–90.PubMedCrossRef

65.

Myhre PL, et al. Prognostic value of secretoneurin in patients with acute respiratory failure: data from the FINNALI Study. Clin Chem. 2016;62(10):1380–9.PubMedCrossRef

66.

Hasslacher J, et al. Secretoneurin as a marker for hypoxic brain injury after cardiopulmonary resuscitation. Intensive Care Med. 2014;40(10):1518–27.PubMedCrossRef

67.

Røsjø H, et al. Effect of short- and long-term physical activities on circulating granin protein levels. Regul Pept. 2013;185:14–9.PubMedCrossRef

68.

Bauer SH, et al. Chromogranin A from bovine adrenal medulla: molecular characterization of glycosylations, phosphorylations, and sequence heterogeneities by mass spectrometry. Anal Biochem. 1999;274(1):69–80.PubMedCrossRef

69.

O'Connor DT, Deftos LJ. Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med. 1986;314(18):1145–51.PubMedCrossRef

70.

Pasqua T, et al. Full-length human chromogranin-A cardioactivity: myocardial, coronary, and stimulus-induced processing evidence in normotensive and hypertensive male rat hearts. Endocrinology. 2013;154(9):3353–65.PubMedCrossRef

71.

Røsjø H, et al. Influence of glycosylation on diagnostic and prognostic accuracy of N-terminal pro-B-type natriuretic peptide in acute dyspnea: data from the Akershus Cardiac Examination 2 Study. Clin Chem. 2015;61(8):1087–97.PubMedCrossRef

72.

Jiang J, et al. Effect of sialylated O-glycans in pro-brain natriuretic peptide stability. Clin Chem. 2010;56(6):959–66.PubMedPubMedCentralCrossRef

73.

Kennedy BP, et al. Mechanism of cardiovascular actions of the chromogranin A fragment catestatin in vivo. Peptides. 1998;19(7):1241–8.PubMedCrossRef

74.

Mazza R, et al. Catestatin (chromogranin A344–364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart. Am J Physiol Heart Circ Physiol. 2008;295(1):H113–22.PubMedPubMedCentralCrossRef

75.

Gayen JR, et al. Global disturbances in autonomic function yield cardiovascular instability and hypertension in the chromogranin a null mouse. Endocrinology. 2009;150(11):5027–35.PubMedPubMedCentralCrossRef

76.

Dev NB, et al. Chromogranin A and the autonomic system: decomposition of heart rate variability and rescue by its catestatin fragment. Endocrinology. 2010;151(6):2760–8.PubMedPubMedCentralCrossRef

77.

Imbrogno S, et al. The catecholamine release-inhibitory peptide catestatin (chromogranin A344–363) modulates myocardial function in fish. J Exp Biol. 2010;213(Pt 21):3636–43.

78.

Penna C, et al. Catestatin improves post-ischemic left ventricular function and decreases ischemia/reperfusion injury in heart. Cell Mol Neurobiol. 2010;30(8):1171–9.PubMedPubMedCentralCrossRef

79.

Bassino E, et al. Catestatin exerts direct protective effects on rat cardiomyocytes undergoing ischemia/reperfusion by stimulating PI3K-Akt-GSK3beta pathway and preserving mitochondrial membrane potential. PLoS One. 2015;10(3):e0119790.PubMedPubMedCentralCrossRef

80.

Angelone T, Mazza R, Cerra MC. Chromogranin-A: a multifaceted cardiovascular role in health and disease. Curr Med Chem. 2012;19(24):4042–50.PubMedCrossRef

81.

Perrelli MG, et al. Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling. Pflugers Arch. 2013;465(7):1031–40.PubMedCrossRef

82.

83.

Corti A, et al. Vasostatins exert negative inotropism in the working heart of the frog. Ann N Y Acad Sci. 2002;971:362–5.PubMedCrossRef

84.

Tota B, et al. The novel chromogranin A-derived serpinin and pyroglutaminated serpinin peptides are positive cardiac beta-adrenergic-like inotropes. FASEB J. 2012;26(7):2888–98.PubMedPubMedCentralCrossRef

85.

Cappello S, et al. Human recombinant chromogranin A-derived vasostatin-1 mimics preconditioning via an adenosine/nitric oxide signaling mechanism. Am J Physiol Heart Circ Physiol. 2007;293(1):H719–27.PubMedCrossRef

86.

Stavrakis S, et al. Antiarrhythmic effects of vasostatin-1 in a canine model of atrial fibrillation. J Cardiovasc Electrophysiol. 2012;23(7):771–7.PubMedCrossRef

87.

Yu M, et al. Overexpression of vasostatin-1 protects hypoxia/reoxygenation injuries in cardiomyocytes independent of endothelial cells. Cardiovasc Ther. 2012;30(3):145–51.PubMedCrossRef

88.

Salem S, et al. Identification of the vasoconstriction-inhibiting factor (VIF), a potent endogenous cofactor of angiotensin II acting on the angiotensin II type 2 receptor. Circulation. 2015;131(16):1426–34.PubMedCrossRef

89.

Wang D, et al. Vasostatin-1 stops structural remodeling and improves calcium handling via the eNOS-NO-PKG pathway in rat hearts subjected to chronic beta-adrenergic receptor activation. Cardiovasc Drugs Ther. 2016;30(5):455–64.PubMedCrossRef

90.

Filice, E., et al., Chromofungin, CgA47-66-derived peptide, produces basal cardiac effects and postconditioning cardioprotective action during ischemia/reperfusion injury. Peptides, 2015. 71: p. 40-8.

91.

92.

Schgoer W, et al. Gene therapy with the angiogenic cytokine secretoneurin induces therapeutic angiogenesis by a nitric oxide-dependent mechanism. Circ Res. 2009;105(10):994–1002.PubMedCrossRef

93.

Albrecht-Schgoer K, et al. The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells. Circulation. 2012;126(21):2491–501.PubMedCrossRef

94.

Schgoer W, et al. Secretoneurin gene therapy improves blood flow in an ischemia model in type 1 diabetic mice by enhancing therapeutic neovascularization. PLoS One. 2013;8(9):e74029.PubMedPubMedCentralCrossRef

95.

Theurl M, et al. Secretoneurin gene therapy improves hind limb and cardiac ischaemia in Apo E(-)/(-) mice without influencing systemic atherosclerosis. Cardiovasc Res. 2015;105(1):96–106.PubMedCrossRef

Title: Glycosylated Chromogranin A: Potential Role in the Pathogenesis of Heart Failure
Authors: Anett H. Ottesen
Geir Christensen
Torbjørn Omland
Helge Røsjø
Publication date: 01-12-2017
Publisher: Springer US
Published in: Current Heart Failure Reports / Issue 6/2017
Print ISSN: 1546-9530
Electronic ISSN: 1546-9549
DOI: https://doi.org/10.1007/s11897-017-0360-x

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