135CgA cleavage, at the level of the multiple pairs of dibasic sites which enrich its
sequence, gives rise several bioactive fragments, which exert a broad spectrum of regu-
latory activities by influencing endocrine, cardiovascular, and immune systems. These
include the dysglycemic hormone pancreastatin (Tatemoto et al. 1986 ), the vasodila-
tors vasostatin 1 (VS-1) and vasostatin 2 (VS-2) (Aardal and Helle 1992 ; Aardal et al.
1993 ), the antimicrobial agent chromacin (Strub et al. 1996 ), the catecholamine release-
inhibitory peptide catestatin (CST) (Mahata et al. 1997 , 2003 , 2004 ), the antifungal
fragment chromofungin (Lugardon et al. 2001 ) and its well- conserved domains WE-14,
parastatin, and GE-25, whose role is currently under searching, and the recently identi-
fied serpinin peptides (Serp and pGlu-Serp) with important roles in neuroendocrine
cells granule biogenesis and cell death (Koshimizu et al. 2011 ).
For cardiovascular interest, the N-terminal CgA derived peptides VS-1 and VS-2,
corresponding to the CgA amino acids 1–76 (VS-1) and 1–113 (VS-2), respectively,
and the middle domain CST (CgA344–364) are under intensive investigations for
their role as anti-adrenosympathetic stabilizers in cardiovascular homeostasis and
anti-ischemic cardioprotection. In fact, it has been demonstrated that both in mam-
malian and non mammalian vertebrates they are able to modulate basal cardiac
performance and to exert anti-adrenergic cardio-suppressive actions which would
protect the heart against excessive systemic and/or intra-cardiac excitatory stimuli
(Tota et al. 2003 ; Corti et al. 2002 , 2004 ; Imbrogno et al. 2004 , 2010 ; Cerra et al.
2006 ; Angelone et al. 2008 ; Mazza et al. 2008 , 2015 ). These experimental evidences
have lead to propose CgA as precursor of different hormone peptides which func-
tion as novel cardiac modulators also able to protect the heart against excessive
systemic and/or intra-cardiac excitatory stimuli.
On the basis of these premises, in this review we will summarize present knowl-
edge regarding the influence exerted by the CgA-derived peptides VS-1, VS-2 and
CST on fish and amphibian hearts, which, in the absence of other data, is mostly
based on our own studies. By examining mechanistically the transduction pathways
activated, we will consider aspects of uniformity and species-specific diversity in
the exerted cardiotropism. Moreover, the role of these peptides as cardio-protective
agents able to counteract the effects of excessive systemic and/or intra-cardiac
excitatory stimuli will be discussed.
The purpose is to provide the basis for a comprehensive picture of the potentials
of the CgA-derived peptides in the cardiac homeostasis of non mammalian
vertebrates.
2 Vasostatins
Vasostatins (VSs), together with pancreastatin, parastatin, and catestatin, are the
main biologically active peptides generated by the proteolytic processing of
CgA. Named ‘vasostatins’ for their ability to relax vessels precontracted by high
endothelin-1 (ET-1) and potassium concentrations (Aardal and Helle 1992 ), they
have been identified in both poikilotherm (frog) and homeotherm (rat, pig, bovine,
Comparative Aspects of CgA-Derived Peptides in Cardiac Homeostasis