Abstract
Half a century after the discovery of chromogranin A as a secreted product of the catecholamine storage granules in the bovine adrenal medulla, the physiological role for the circulating pool of this protein has been recently coined, namely as an important player in vascular homeostasis. While the circulating chromogranin A since 1984 has proved to be a significant and useful marker of a wide range of pathophysiological and pathological conditions involving the diffuse neuroendocrine system, this protein has now been assigned a physiological “raison d’etre” as a regulator in vascular homeostasis. Moreover, chromogranin A processing in response to tissue damage and blood coagulation provides the first indication of a difference in time frame of the regulation of angiogenesis evoked by the intact chromogranin A and its two major peptide products, vasostatin-1 and catestatin. The impact of these discoveries on vascular homeostasis, angiogenesis, cancer, tissue repair and cardio-regulation will be discussed.
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References
Banks P, Helle KB (1965) The release of protein from the stimulated adrenal medulla. Biochem J 97:40C–41C
Blaschko H, Comline RS, Schneider FH, Silver M, Smith AD (1967) Secretion of a chromaffin granule protein, chromogranin, from the adrenal gland after splanchnic stimulation. Nature 215:58–59
O’Connor DT, Bernstein KN (1984) Radioimmunoassay of chromogranin A in plasma as a measure of exocytotic sympathoadrenal activity in normal subjects and patients with pheochromocytoma. N Engl J Med 311:764–770
Iacangelo A, Affolter HU, Eiden LE, Herbert E, Grimes M (1986) Bovine chromogranin A sequence and distribution of its messenger RNA in endocrine tissues. Nature 323:82–86
Benedum UM, Baeuerle PA, Konecki DS, Frank R, Powell J, Mallet J, Huttner WB (1986) The primary structure of bovine chromogranin A: a representative of a class of acidic secretory proteins common to a variety of peptidergic cells. EMBO J 5:1495–1502
Tatemoto K, Efendic S, Mutt V, Makk G, Feistner GJ, Barchas JD (1986) Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion. Nature 324:476–478
Eiden LE (1987) Is chromogranin a prohormone? Nature 325:301
Huttner WB, Benedum UM (1987) Chromogranin A and pancreastatin. Nature 325:305
Aardal S, Helle KB (1992) The vasoinhibitory activity of bovine chromogranin A fragment (vasostatin) and its independence of extracellular calcium in isolated segments of human blood vessels. Regul Pept 41:9–18
Mahata SK, O’Connor DT, Mahata M, Yoo SH, Taupenot L, Wu H, Gill BM, Parmer RJ (1997) Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist. J Clin Invest 100:1623–1633
Helle KB, Corti A, Metz-Boutigue MH, Tota B (2007) The endocrine role for chromogranin A: a prohormone for peptides with regulatory properties. Cell Mol Life Sci 64:2863–2886
Corti A, Ferrero E (2012) Chromogranin A and the endothelial barrier function. Curr Med Chem 19:4051–4058
Crippa L, Bianco M, Colombo B, Gasparri AM, Ferrero E, Loh YP, Curnis F, Corti A (2013) A new chromogranin A-dependent angiogenic switch activated by thrombin. Blood 121:392–402
Helle KB (2010) The chromogranin A-derived peptides vasostatin-I and catestatin as regulatory peptides for cardiovascular functions. Cardiovasc Res 85:9–16
Theurl M, Schgoer W, Albrecht K, Jeschke J, Egger M, Beer AG, Vasiljevic D, Rong S, Wolf AM, Bahlmann FH et al (2010) The neuropeptide catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. Circ Res 107:1326–1335
Pasqua T, Corti A, Gentile S, Pochini L, Bianco M, Metz-Boutigue MH, Cerra MC, Tota B, Angelone T (2013) Full-length human Chromogranin-A cardioactivity: myocardial, coronary and stimulus-induced processing evidence in normotensive and hypertensive male rat hearts. Endocrinology 154(9):3353–3365
Ji L, Pei ZQ, Ma DF, Zhang J, Su JS, Gao XD, Xue WZ, Chen XP, Wang WS (2012) Prognostic value of circulating catestatin levels for in-hospital heart failure in patients with acute myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi 40:914–919
Meng L, Wang J, Ding WH, Han P, Yang Y, Qi LT, Zhang BW (2013) Plasma catestatin level in patients with acute myocardial infarction and its correlation with ventricular remodelling. Postgrad Med J 89:193–196
O’Connor DT, Kailasam MT, Kennedy BP, Ziegler MG, Yanaihara N, Parmer RJ (2002) Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension. J Hypertens 20:1335–1345
Fournier I, Gaucher D, Chich JF, Bach C, Shooshtarizadeh P, Picaud S, Bourcier T, Speeg-Schatz C, Strub JM, Van Dorsselaer A et al (2011) Processing of chromogranins/secretogranin in patients with diabetic retinopathy. Regul Pept 167:118–124
Schneider F, Bach C, Chung H, Crippa L, Lavaux T, Bollaert PE, Wolff M, Corti A, Launoy A, Delabranche X et al (2012) Vasostatin-I, a chromogranin A-derived peptide, in non-selected critically ill patients: distribution, kinetics, and prognostic significance. Intensive Care Med 38:1514–1522
Liu L, Ding W, Zhao F, Shi L, Pang Y, Tang C (2013) Plasma levels and potential roles of catestatin in patients with coronary heart disease. Scand Cardiovasc J 47:217–224
Metz-Boutigue MH, Garcia-Sablone P, Hogue-Angeletti R, Aunis D (1993) Intracellular and extracellular processing of chromogranin A. Determination of cleavage sites. Eur J Biochem 217:247–257
Belloni D, Scabini S, Foglieni C, Veschini L, Giazzon A, Colombo B, Fulgenzi A, Helle KB, Ferrero ME, Corti A et al (2007) The vasostatin-I fragment of chromogranin A inhibits VEGF-induced endothelial cell proliferation and migration. FASEB J 21:3052–3062
Ferrero E, Scabini S, Magni E, Foglieni C, Belloni D, Colombo B, Curnis F, Villa A, Ferrero ME, Corti A (2004) Chromogranin A protects vessels against tumor necrosis factor alpha-induced vascular leakage. FASEB J 18(3):554–555
Dondossola E, Crippa L, Colombo B, Ferrero E, Corti A (2012) Chromogranin A regulates tumor self-seeding and dissemination. Cancer Res 72:449–459
Blois A, Srebro B, Mandalà M, Corti A, Helle KB, Serck-Hanssen G (2006) The chromogranin A peptide vasostatin-I inhibits gap formation and signal transduction mediated by inflammatory agents in cultured bovine pulmonary and coronary arterial endothelial cells. Regul Pept 135:78–84
Breslin JW, Pappas PJ, Cerveira JJ, Hobson RW 2nd, Duran WN (2003) VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide. Am J Physiol Heart Circ Physiol 284:H92–H100
Koss M, Pfeiffer GR 2nd, Wang Y, Thomas ST, Yerukhimovich M, Gaarde WA, Doerschuk CM, Wang Q (2006) Ezrin/radixin/moesin proteins are phosphorylated by TNF-alpha and modulate permeability increases in human pulmonary microvascular endothelial cells. J Immunol 176:1218–1227
Pieroni M, Corti A, Tota B, Curnis F, Angelone T, Colombo B, Cerra MC, Bellocci F, Crea F, Maseri A (2007) Myocardial production of chromogranin A in human heart: a new regulatory peptide of cardiac function. Eur Heart J 28:1117–1127
Ceconi C, Ferrari R, Bachetti T, Opasich C, Volterrani M, Colombo B, Parrinello G, Corti A (2002) Chromogranin A in heart failure; a novel neurohumoral factor and a predictor for mortality. Eur Heart J 23:967–974
Goetze JP, Hilsted LM, Rehfeld JF, Alehagen U (2014) Plasma chromogranin A is a marker of death in elderly patients presenting with symptoms of heart failure. Endocr Connect 3:47–56
Jansson AM, Rosjo H, Omland T, Karlsson T, Hartford M, Flyvbjerg A, Caidahl K (2009) Prognostic value of circulating chromogranin A levels in acute coronary syndromes. Eur Heart J 30:25–32
Tota B, Gentile S, Pasqua T, Bassino E, Koshimizu H, Cawley NX, Cerra MC, Loh YP, Angelone T (2012) The novel chromogranin A-derived serpinin and pyroglutaminated serpinin peptides are positive cardiac beta-adrenergic-like inotropes. FASEB J 26:2888–2898
Angelone T, Quintieri AM, Brar BK, Limchaiyawat PT, Tota B, Mahata SK, Cerra MC (2008) The antihypertensive chromogranin a peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism. Endocrinology 149:4780–4793
Cerra MC, De Iuri L, Angelone T, Corti A, Tota B (2006) Recombinant N-terminal fragments of chromogranin-A modulate cardiac function of the Langendorff-perfused rat heart. Basic Res Cardiol 101:43–52
Loh YP, Cheng Y, Mahata SK, Corti A, Tota B (2012) Chromogranin A and derived peptides in health and disease. J Mol Neurosci 48:347–356
Corti A, Ferrari R, Ceconi C (2000) Chromogranin A and tumor necrosis factor-alpha (TNF) in chronic heart failure. Adv Exp Med Biol 482:351–359
Ben-Haim S, Gacinovic S, Israel O (2009) Cardiovascular infection and inflammation. Semin Nucl Med 39:103–114
Tatasciore A, Zimarino M, Renda G, Zurro M, Soccio M, Prontera C, Emdin M, Flacco M, Schillaci G, De Caterina R (2008) Awake blood pressure variability, inflammatory markers and target organ damage in newly diagnosed hypertension. Hypertens Res 31:2137–2146
Anaya-Prado R, Toledo-Pereyra LH (2002) The molecular events underlying ischemia/reperfusion injury. Transplant Proc 34:2518–2519
Rodriguez-Sinovas A, Abdallah Y, Piper HM, Garcia-Dorado D (2007) Reperfusion injury as a therapeutic challenge in patients with acute myocardial infarction. Heart Fail Rev 12:207–216
Cappello S, Angelone T, Tota B, Pagliaro P, Penna C, Rastaldo R, Corti A, Losano G, Cerra MC (2007) Human recombinant chromogranin A-derived vasostatin-1 mimics preconditioning via an adenosine/nitric oxide signaling mechanism. Am J Physiol Heart Circul Physiol 293:H719–H727
Penna C, Tullio F, Perrelli MG, Mancardi D, Pagliaro P (2012) Cardioprotection against ischemia/reperfusion injury and chromogranin A-derived peptides. Curr Med Chem 19:4074–4085
Cappello S, Angelone T, Tota B, Pagliaro P, Penna C, Rastaldo R, Corti A, Losano G, Cerra MC (2007) Human recombinant chromogranin A-derived vasostatin-1 mimics preconditioning via an adenosine/nitric oxide signaling mechanism. Am J Physiol Heart Circ Physiol 293:H719–H727
Penna C, Alloatti G, Gallo MP, Cerra MC, Levi R, Tullio F, Bassino E, Dolgetta S, Mahata SK, Tota B et al (2010) Catestatin improves post-ischemic left ventricular function and decreases ischemia/reperfusion injury in heart. Cell Mol Neurobiol 30:1171–1179
Brar BK, Helgeland E, Mahata SK, Zhang K, O’Connor DT, Helle KB, Jonassen AK (2010) Human catestatin peptides differentially regulate infarct size in the ischemic-reperfused rat heart. Regul Pept 165:63–70
Glattard E, Angelone T, Strub JM, Corti A, Aunis D, Tota B, Metz-Boutigue MH, Goumon Y (2006) Characterization of natural vasostatin-containing peptides in rat heart. FEBS J 273:3311–3321
Biswas N, Curello E, O’Connor DT, Mahata SK (2010) Chromogranin/secretogranin proteins in murine heart: myocardial production of chromogranin A fragment catestatin (Chga(364–384)). Cell Tissue Res 342:353–361
Foster W, Carruthers D, Lip GY, Blann AD (2009) Relationships between endothelial, inflammatory and angiogenesis markers in rheumatoid arthritis: implications for cardiovascular pathophysiology. Thromb Res 123:659–664
Capellino S, Lowin T, Angele P, Falk W, Grifka J, Straub RH (2008) Increased chromogranin A levels indicate sympathetic hyperactivity in patients with rheumatoid arthritis and systemic lupus erythematosus. J Rheumatol 35:91–99
Di Comite G, Rossi CM, Marinosci A, Lolmede K, Baldissera E, Aiello P, Mueller RB, Herrmann M, Voll RE, Rovere-Querini P et al (2009) Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-alpha-elicited endothelial activation. J Leukoc Biol 85:81–87
Portela-Gomes GM, Grimelius L, Wilander E, Stridsberg M (2010) Granins and granin-related peptides in neuroendocrine tumours. Regul Pept 165:12–20
Taupenot L, Harper KL, O’Connor DT (2003) The chromogranin-secretogranin family. N Engl J Med 348:1134–1149
Guerin M, Guillemot J, Thouennon E, Pierre A, El-Yamani FZ, Montero-Hadjadje M, Dubessy C, Magoul R, Lihrmann I, Anouar Y et al (2010) Granins and their derived peptides in normal and tumoral chromaffin tissue: implications for the diagnosis and prognosis of pheochromocytoma. Regul Pept 165:21–29
Corti A (2010) Chromogranin A and the tumor microenvironment. Cell Mol Neurobiol 30:1163–1170
Stridsberg M, Eriksson B, Oberg K, Janson ET (2003) A comparison between three commercial kits for chromogranin A measurements. J Endocrinol 177:337–341
Colombo B, Curnis F, Foglieni C, Monno A, Arrigoni G, Corti A (2002) Chromogranin a expression in neoplastic cells affects tumor growth and morphogenesis in mouse models. Cancer Res 62:941–946
Mandala M, Stridsberg M, Helle KB, Serck-Hanssen G (2000) Endothelial handling of chromogranin A. Adv Exp Med Biol 482:167–178
Angeletti RH, Aardal S, Serck-Hanssen G, Gee P, Helle KB (1994) Vasoinhibitory activity of synthetic peptides from the amino terminus of chromogranin A. Acta Physiol Scand 152:11–19
Russell J, Gee P, Liu SM, Angeletti RH (1994) Inhibition of parathyroid hormone secretion by amino-terminal chromogranin peptides. Endocrinology 135:337–342
Ramella R, Boero O, Alloatti G, Angelone T, Levi R, Gallo MP (2010) Vasostatin 1 activates eNOS in endothelial cells through a proteoglycan-dependent mechanism. J Cell Biochem 110:70–79
Dondossola E, Gasparri A, Bachi A, Longhi R, Metz-Boutigue MH, Tota B, Helle KB, Curnis F, Corti A (2010) Role of vasostatin-1 C-terminal region in fibroblast cell adhesion. Cell Mol Life Sci 67:2107–2118
Curnis F, Gasparri A, Longhi R, Colombo B, D’Alessio S, Pastorino F, Ponzoni M, Corti A (2012) Chromogranin A binds to αvβ6-integrin and promotes wound healing in mice. Cell Mol Life Sci 69:2791–2803
Thomas GJ, Nystrom ML, Marshall JF (2006) Alphavbeta6 integrin in wound healing and cancer of the oral cavity. J Oral Pathol Med 35:1–10
Busk M, Pytela R, Sheppard D (1992) Characterization of the integrin alpha v beta 6 as a fibronectin-binding protein. J Biol Chem 267:5790–5796
Bandyopadhyay A, Raghavan S (2009) Defining the role of integrin alphavbeta6 in cancer. Curr Drug Targets 10:645–652
Koivisto L, Larjava K, Hakkinen L, Uitto VJ, Heino J, Larjava H (1999) Different integrins mediate cell spreading, haptotaxis and lateral migration of HaCaT keratinocytes on fibronectin. Cell Adhes Commun 7:245–257
Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8:604–617
Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10:9–22
Acknowledgments
This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 14338 and 9965) of Italy.
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Helle, K.B., Corti, A. Chromogranin A: a paradoxical player in angiogenesis and vascular biology. Cell. Mol. Life Sci. 72, 339–348 (2015). https://doi.org/10.1007/s00018-014-1750-9
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DOI: https://doi.org/10.1007/s00018-014-1750-9