Chromogranins: from discovery to current times.

The discovery in 1953 of the chromaffin granules as co-storage of catecholamines and ATP was soon followed by identification of a range of uniquely acidic proteins making up the isotonic vesicular storage complex within elements of the diffuse sympathoadrenal system. In the mid-1960s, the enzymatically inactive, major core protein, chromogranin A was shown to be exocytotically discharged from the stimulated adrenal gland in parallel with the co-stored catecholamines and ATP. A prohormone concept was introduced when one of the main storage proteins collectively named granins was identified as the insulin release inhibitory polypeptide pancreastatin.

Granin-derived peptides.

The granin family comprises altogether 7 different proteins originating from the diffuse neuroendocrine system and elements of the central and peripheral nervous systems. The family is dominated by three uniquely acidic members, namely chromogranin A (CgA), chromogranin B (CgB) and secretogranin II (SgII). Since the late 1980s it has become evident that these proteins are proteolytically processed, intragranularly and/or extracellularly into a range of biologically active peptides; a number of them with regulatory properties of physiological and/or pathophysiological significance.

Chromogranin A: a paradoxical player in angiogenesis and vascular biology.

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 chromogranin A- derived N-terminal peptide vasostatin-I: In vivo effects on cardiovascular variables in the rabbit.

This study is the first to report on vascular effect of the chromogranin A derived Vasostatin-I (CgA(1-76)) in vivo. Cardiovascular parameters were recorded in 29 rabbits with sympathetically decentralized right carotid vascular bed. The recombinant human STA CgA(1-78) (VS-1) was infused at 480 μg/kg over 25 min.

Regulatory peptides from chromogranin A and secretogranin II.

This commentary is focusing on novel aspects on the secreted CgA- and SgII-derived peptides, vasostatin-I (bovine and human CgA(1-76), VS-I), WE-14 (CgA(316-329)), catestatin (bovine CgA(344-366), human CgA(352-372), Cts) and the SgII-derived secretoneurin (SgII(180-204)) as significant regulators of inflammatory reactions.

Human catestatin peptides differentially regulate infarct size in the ischemic-reperfused rat heart.

In acute myocardial infarction increased plasma levels of chromogranin A are correlated with decreased survival. At the human chromogranin A gene locus there are two naturally occurring amino acid substitution variants within the catestatin region, i.e.

Chromogranins A and B and secretogranin II as prohormones for regulatory peptides from the diffuse neuroendocrine system.

Chromogranin A (CgA), chromogranin B (CgB), and secretogranin II (SgII) belong to a family of uniquely acidic secretory proteins in elements of the diffuse neuroendocrine system. These "granins" are characterized by numerous pairs of basic amino acids as potential sites for intra- and extragranular processing. In response to adequate stimuli, the granins are coreleased with neurotransmitters and hormones and appear in the circulation as potential modulators of homeostatic processes.

Role of vasostatin-1 C-terminal region in fibroblast cell adhesion.

Fibroblast adhesion can be modulated by proteins released by neuroendocrine cells and neurons, such as chromogranin A (CgA) and its N-terminal fragment vasostatin-1 (VS-1, CgA(1-78)). We have investigated the mechanisms of the interaction of VS-1 with fibroblasts and of its pro-adhesive activity and have found that the proadhesive activity of VS-1 relies on its interaction with the fibroblast membrane via a phospholipid-binding amphipathic alpha-helix located within residues 47-66, as well as on the interaction of the adjacent C-terminal region 67-78, which is structurally similar to ezrin-radixin-moesin-binding phosphoprotein 50 (a membrane-cytoskeleton adapter protein), with other cellular components critical for the regulation of cell cytoskeleton.

Regulatory peptides from chromogranin A and secretogranin II: putative modulators of cells and tissues involved in inflammatory conditions.

Chromogranin A (CgA) and secretogranin II (SgII) of the granin family of uniquely acidic proteins secreted from elements of the diffuse neuroendocrine system are also produced by cells involved in inflammation. CgA and the CgA-derived peptides vasostatin-I and catestatin are products of polymorphonuclear neutrophils accumulating at sites of injury or infections while SgII and the Sg II-derived secretoneurin may contribute to neurogenic inflammation when released from sensory nerve terminals. This review is directed towards vasostatin-I, catestatin and secretoneurin as modulators of cells and tissues associated with inflammatory conditions.

The chromogranin A-derived peptides vasostatin-I and catestatin as regulatory peptides for cardiovascular functions.

A range of inflammatory conditions is associated with pathologically high levels of circulating chromogranin A (CgA). This prohormone belongs to the family of uniquely acidic proteins co-stored and co-secreted with other hormones and peptides from the diffuse neuroendocrine system. Two highly conserved, CgA-derived peptides, vasostatin-I and catestatin, have been implicated as modulators of a wide range of cells and tissues, including those of the cardiovascular system.

Effect of exercise training on chromogranin A and relationship to N-ANP and inflammatory cytokines in patients with chronic heart failure.

Exercise training improves functional parameters in patients with congestive heart failure (CHF). The aim of this study was to establish whether exercise training influence the elevated CgA levels in CHF patients. Plasma CgA was determined at baseline and at peak exercise before and after 12 weeks of training in 25 men (mean age 67+/-8 years) with CHF (NYHA functional class II and III).

The vasostatin-I fragment of chromogranin A inhibits VEGF-induced endothelial cell proliferation and migration.

Unlabelled: A growing body of evidence suggests that chromogranin A (CgA), a secretory protein released by many neuroendocrine cells and frequently used as a diagnostic and prognostic serum marker for a range of neuroendocrine tumors, is a precursor of several bioactive fragments. This work was undertaken to assess whether the N-terminal fragment CgA(1-76) (called vasostatin I) can inhibit the proangiogenic activity of vascular endothelial growth factor (VEGF), a factor involved in tumor growth. The effect of recombinant human vasostatin I (VS-1) on VEGF-induced human umbilical endothelial cells (HUVEC) signaling, proliferation, migration, and organization has been investigated.

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.

The proinflammatory agent tumour necrosis factor alpha (TNFalpha) is one of several agents causing vascular leakage. The N-terminal domain of CgA, vasostatin-I (CgA1-76), has recently been reported to inhibit TNFalpha induced gap formation in human umbilical venous endothelial cells. Here we report on the effect of recombinant human CgA1-78, vasostatin-I, on TNFalpha induced gap formation in two model systems of vascular leakage in arterial endothelial cells of bovine pulmonary (BPAEC) and coronary (BCAEC) origin.

Interactions of chromogranin A-derived vasostatins and monolayers of phosphatidylserine, phosphatidylcholine and phosphatidylethanolamine.

Vasostatin-I (CgA1-76) is a naturally occurring and biologically active N-terminal peptide derived from chromogranin A (CgA), produced and secreted at high concentrations by neuroendocrine tissues and also from a range of neuroendocrine tumors. This study aims to examine the hypothesis that in the absence of classical protein receptors CgA1-76 may, like its two derived peptides CgA1-40 and CgA47-66, perturb the lipid microenvironment of other membrane receptors, as a basis for the largely inhibitory activities of these CgA peptides. The nature of the interactions between phospholipids and vasostatin-derived fragments was studied in the Langmuir film balance apparatus at 37 degrees C.

The granin family of uniquely acidic proteins of the diffuse neuroendocrine system: comparative and functional aspects.

The chromogranins A (CgA) and B (CgB) and secretogranin II (SgII) constitute the main members of a family of uniquely acidic secretory proteins in elements of the diffuse neuroendocrine system. These genetically distinct proteins, CgA, CgB, SgII and the less well known secretogranins III-VII are collectively referred to as 'granins' and characterised by numerous pairs of basic amino acids as potential cleavage sites for processing by the co-stored prohormone converting enzymes PC 1/3 and PC2. This review is directed towards comparative and functional aspects of the granins with emphasis on their phylogenetically conserved sequences.

Chromogranin A-derived peptides: interaction with the rat posterior cerebral artery.

Chromogranin A (CgA), an acidic granule protein of the regulated secretory pathway in the diffuse neuroendocrine system, is postulated to serve as a prohormone for regulatory peptides. Betagranin (rCgA(1-128)), the first N-terminal cleavage product of rat CgA, is 87% homologous to the bovine vasostatin I (bCgA(1-76)), previously shown to be vasoinhibitory in bovine resistance arteries. In this study the vasoactivity of homologous rat and bovine peptides was investigated in the rat posterior cerebral artery.

Influence of vasostatins, the chromogranin A-derived peptides, on the working heart of the eel (Anguilla anguilla): negative inotropy and mechanism of action.

We have studied the effects of exogenous human recombinant Vasostatin-1 (VS-1), Vasostatin-2 (VS-2) and the human Chromogranin A (CGA) 7-57 synthetic peptides on the mechanical performance of the isolated and perfused working eel (Anguilla anguilla) heart. Under basal conditions, the three peptides decreased stroke volume (SV) and stroke work (SW), thus exerting negative inotropism. The VS-1-mediated negative inotropism was abolished by exposure to inhibitors of either Gi/o protein (pertussis toxin; PTx) or M1 muscarinic receptors (Pirenzepine) or calcium (Lantanum and Diltiazem) and potassium (Ba2+, 4-aminopyridine, tetraethylammonium, glibenclamide) channels, while it required an intact endocardial endothelium (EE).

Peptides from the N-terminal domain of chromogranin A (vasostatins) exert negative inotropic effects in the isolated frog heart.

The negative inotropic effects of synthetic peptides derived from the N-terminus of chromogranin A (CgA) were studied in an avascular model of the vertebrate myocardium, the isolated working frog heart (Rana esculenta). The peptides were frog and bovine CgA(4-16) and CgA(47-66), and bovine CgA(1-40) with (CgA(1-40SS)) and without an intact disulfide bridge (CgA(1-40SH)). Under basal cardiac conditions, four of the peptides caused a concentration-dependent negative inotropism that was comparable to the negative inotropy reported for human recombinant vasostatin I (CgA(1-78)) and bovine CgA(7-57).

Catestatin (CgA344-364) stimulates rat mast cell release of histamine in a manner comparable to mastoparan and other cationic charged neuropeptides.

Catestatin (bovine CgA(344-364)) is a cationic peptide, which besides reducing catecholamine secretion from chromaffin cells in vitro also acts a potent vasodilator in the rat in vivo. The alleged histamine releasing effect of catestatin was tested in vitro in rat mast cells. The most active domain of catestatin (bovine CgA(344-358): RSMRLSFRARGYGFR) caused concentration-dependent (0.

N-terminal chromogranin-derived peptides as dilators of bovine coronary resistance arteries.

N-terminal peptides of chromogranin A and B (CGA and CGB) were compared for dilator responses in isolated bovine coronary arteries (bCoA), measuring diameter changes as a function of pressure. bCoA developed and maintained myogenic tone (MYT) at approximately 20% from 50 to 150 mm Hg. In contrast to CGB(1-40), CGA(1-40) and CGA(1-76) (VS-I) both displayed significant intrinsic vasodilator effects.