151and resistance vessels (Brekke et al. 2002 ). Initially identified as a potent endogenous
nicotinic–cholinergic antagonist, Catestatin (CgA344–364; CST) has subsequently
been shown to play a role as a novel regulator of cardiac function and blood pres-
sure. Several findings indeed suggest that CST may act as an endogenous vascular
tone regulator, possibly involved in predisposition to hypertension, and a modulator
of cardiorespiratory control in the brain stem (Fung et al. 2010 ; Mahapatra et al.
2005 ; Mahata et al. 2010 ; Rao et al. 2007 ). Besides VSs and CST, Chromofungin
(Chr: CgA47–66) and Serpinin, two other CgA-derived peptides displaying cardio-
vascular modulatory activities, have been recently isolated and characterized (Filice
et al. 2015 ; Tota et al. 2012 ). In addition, full-length CgA itself exerts negative
inotropic and lusitropic effects on mammalian heart (Pasqua et al. 2013 ). In light of
the fact that CgA is produced by human myocardium (Pieroni et al. 2007 ), and the
broad spectrum of cardiovascular effects of CgA and derived peptides, these media-
tors may represent key players in neuroendocrine regulation of cardiac function and
potential therapeutic targets in cardiovascular diseases. This chapter focuses on the
recently discovered signalling pathways activated by CgA-derived peptides in car-
diomyocytes and endothelial cells, giving insights into the mechanisms at the basis
of their inotropic and cardioprotective effects. The effects exerted by CgA-derived
peptides on the cardiovascular system have been reviewed in several recent papers
(Angelone et al. 2012a; Di Comite and Morganti 2011 ; Fornero et al. 2012 ; Helle
2010 ; Helle and Corti 2015 ; Mazza et al. 2015 ; Tota et al. 2014 ).
2 Cardiac Effects of CgA-Derived Peptides
Taken together, the abovementioned findings indicate a role for CgA-derived pep-
tides as endogenous regulators of cardiovascular system, mainly acting on vascular
tone. Moreover, in vivo studies also suggested a physiological role of VSs and CST
as inotropic regulators. However, it is difficult to establish whether the reduction of
blood pressure observed in vivo experiments is due to a direct effect on cardiac
contractility, rather than on vasodilation and reduced afterload, or secondary to
reduced catecholamine secretion. To investigate whether CgA-derived peptides are
able to directly modulate cardiac inotropism, their effects were tested on ex-vivo
and in vitro cardiac preparations such as the isolated perfused heart, the papillary
muscle and isolated cardiac cells.
2.1 Vasostatins
The cardiac effects of VSs were initially tested on the frog (Corti et al. 2002 , 2004 )
and the eel heart (Imbrogno et al. 2004 ). On both preparations, VSs exerted an
inhibitory effect on basal cardiac performance and counteracted the positive inotro-
pism induced by adrenergic stimulation. Interestingly, while in the frog heart the
Signalling Pathways of CgA-Derived Peptides in Cardiac and Endothelial Cells