85Imbrogno et al. 2004 ; Corti et al. 2004 ), inhibits parathyroid hormone secretion
(Russell et al. 1994 ), is neurotoxic in neuronal/microglial cell cultures (Ciesielski-
Treska et al. 1998 ) and induces antibacterial/antifungal effects (Helle et al. 2007 ;
Lugardon et al. 2000 ). Another fragment corresponding to residues 248–293, called
pancreastatin, regulates glucose and lipid metabolism (Zhang et al. 2006 ; O’Connor
et al. 2005 ; Sanchez-Margalet et al. 2010 ; Gayen et al. 2009 ), whereas a peptide
corresponding to residues 352–372, called catestatin, is a potent inhibitor of
nicotinic- cholinergic-stimulated catecholamine secretion, acts as a vasodilator in
rats and humans, inhibits the inotropic and lusitropic properties of the rodent heart,
induces chemotaxis, stimulates rat mast cells to release histamine, and acts as an
antimicrobial and antimalarial peptide (Mahata et al. 2010 ). Finally, peptides
derived from proteolytic cleavage of the penultimate and the last pair of basic resi-
dues at the C-terminus of CgA, called serpinins, have protective effects against
oxidative stress on neurons and pituitary cells and enhance both myocardial con-
tractility and relaxation (Loh et al. 2012 ).
CgA may also work as a negative modulator of cell adhesion and as a precursor
of positive modulators, depending on proteolytic processing. For instance, CgA,
isolated from human pheochromocytomas, inhibits the adhesion of human and
mouse fibroblasts to plates coated with collagen I, collagen IV, or with fibronectin
(Colombo et al. 2002a; Gasparri et al. 1997 ; Ratti et al. 2000a), whereas the recom-
binant CgA fragment 1–78 promotes fibroblast adhesion (Lugardon et al. 2000 ;
Gasparri et al. 1997 ; Dondossola et al. 2010 ). CgA1-78-dependent cytoskeletal
rearrangements and changes in cell adhesion have been observed also with smooth
muscle cells, cardiomyocytes, keratinocytes and endothelial cells (Colombo et al.
2002a; Gasparri et al. 1997 ; Curnis et al. 2012 ; Angelone et al. 2010 ; Ratti et al.
2000b). Of note, the region 45–78 of this fragment is crucial for this activity: this
region contains an RGD site capable of interacting with αvβ 6 integrin on keratino-
cytes, and is followed by an amphipathic α-helix (residues 47–66), 100%-conserved
in human, porcine, bovine, equine and mouse CgA (Simon and Aunis 1989 ; Turquier
et al. 1999 ). In addition, this region contains the highly conserved hydrophilic resi-
dues 67–78, which share strong sequence and structural similarity with ezrin-
radixin- moesin binding phosphoprotein 50 (EBP50), a protein that works as a
molecular linkage between membrane-cytoskeleton adapter proteins and the cyto-
plasmic domain of various membrane proteins and receptors (Dondossola et al.
2010 ; Bretscher et al. 2002 ).
4 Role of CgA and Its Fragments in Preserving
the Endothelial Barrier Integrity
The endothelium forms a semi-permeable barrier that regulates blood-tissue
exchange of plasma fluid and proteins by trans-cellular and para-cellular transport
mechanisms (Komarova and Malik 2010 ). While the trans-endothelial pathway
Chromogranin A in Endothelial Homeostasis and Angiogenesis