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3 Catestatin
CST (human CgA352–372, bovine CgA344–364) is a 21 amino acid cationic and
hydrophobic peptide product of CgA proteolysis, co-secreted and co-released with
CgA and CAs. It acts as an endogenous non-competitive inhibitor of nicotine-
evoked catecholamine secretion (Mahata et al. 1997 ; Herrero et al. 2002 ). In addi-
tion, it prevents the nicotinic desensitization of catecholamine release from
chromaffin cells (Mahata et al. 1999 ) and, in vivo, it blocks stimulation of both
secretion and transcription of its precursor CgA (Mahata et al. 2003 ). Plasma level
of CST are significantly lower in patients with essential hypertension and in normo-
tensive subjects with family history of hypertension (O’Connor et al. 2002 ).
Consistent with human studies, genetic ablation of ChgA gene results in high blood
pressure in mice (Mahapatra et al. 2005 ). Three biologic variants of CST with vary-
ing effects on adrenergic inhibition have been identified with the following order of
potency: Pro370Leu > wildtype(WT) > Gly364Ser > Arg374Gln (Mahata et al.
2004 ; Wen et al. 2004 ). In vivo, the CST Gly364Ser variant causes profound changes
in human autonomic activity, both at the level of the parasympathetic and sympa-
thetic branches, and seems to reduce risk of developing hypertension, especially in
men (Rao et al. 2007 ).
CST is highly conserved in mammals, with a great homology between human
and mouse (approximately 86%); moreover, human CST shows a moderate homol-
ogy with non mammalian vertebrates: 38% with jungle fowl, 33% with frog, and
approximately 19% with zebrafish (Bartolomucci et al. 2011 ).
3.1 Cardiac Effects Under Basal and ISO-Stimulated
Conditions
On the perfused working frog (Mazza et al. 2008 ) and eel (Imbrogno et al. 2010 )
hearts, CST (bovine CgA344–364) acts as a cardio-depressing agent in a dose-
dependent manner (11–165 nmol/l) and counteracts the ISO-induced cardio-
stimulatory effect through a non-competitive antagonism. In addition, in the frog
heart CST is able to abolish the endothelin-1 (ET-1)-induced positive inotropism,
but does not affect the ET-1-dependent negative effect, the latter being consistent
with a convergent signalling pathway for both ET-1 and CST (Table 1 ). As in eel
and frog hearts, also in the rat heart (Angelone et al. 2008 ), CST directly suppresses
the mechanical performance of both non-stimulated and adrenergically stimulated
preparations, supporting the ubiquitous cardio-depressive action of this peptide in
vertebrates. Of note, in the Langendorff perfused rat heart, human CST variants
counteracted the positive inotropic and lusitropic effects of ISO with different
potency and counteracted the positive inotropism and lusitropism and the coronary
constriction of ET-1, pointing them as important components of a homeostatic
A. Gattuso et al.