181the blockade of Adenosine type 1 (A 1 ) receptors, thus suggesting a peculiarity in
VS-1 mechanism of action. VS-1 activity results mediated by two different path-
ways that converge on PKC: one is mediated by NO release, and the other is medi-
ated by A 1 receptors. Similarly, to preconditioning ischemia, VS-1 may be considered
a stimulus strong enough to trigger the two pathways, which may converge on
PKC. The lack of a cellular receptor for VS-1 (Gallo et al. 2007 ; Ramella et al.
2010 ) can induce the infused VS-1 to interfere with other membrane receptors
(Cappello et al. 2007 ). Importantly, between VS-1 infusion and 30-min ischemia
there was a wash-out period which allowed the recovery from inotropic effect.
Therefore, cardioprotection was not due to a reduction of oxygen consumption
because of cardiac inotropic depression.
Recently in an in vitro trans-well co-colture model of cardiomyocyte-endothelial
cells was demonstrated that VS-1 exerts protective effects directly on the cardiomyo-
cytes or indirectly by cardiomyocyte-endothelial cells interaction (Liu et al. 2014 ).
These data emphasize the potential importance of the release of CgA as a mecha-
nism of the cardiac system to protect itself against I/R injury and, eventually, against
sympathetic overstimulation. Actually, increased plasma levels of CgA are present
in patients after myocardial infarction (Wang et al. 2011 ).
Importantly, in acute myocardial infarction (AMI) patients an initial reduction
with a subsequent increase in catestatin plasma levels has been recently reported
(Wang et al. 2011 ). The increased levels of catestatin and its precursor, CgA, are
more supportive of the potential importance of the release of CgA and derivatives as
attempt to protect the heart against I/R injury. Since the majority of I/R damage
occurs in the early reperfusion, we wondered whether a supplementation of VS-1 or
catestatin in the early reperfusion phase may protect the heart against reperfusion
injury. In our laboratory, we observed that VS-1 does not protect when given in post-
ischemic phase (unpublished observations). On the contrary, catestatin only given in
reperfusion resulted highly protective against I/R damages (Penna et al. 2010a).
3.2 Catestatin
In humans, Catestatin (CST), was initially studied as an important factor in blood
pressure control (Angelone et al. 2008 ; O’Connor et al. 2002 ). However, a compara-
tive study has recently demonstrated that the plasma levels of CST in healthy humans
and in individuals with coronary heart disease are significantly different and corre-
lated somehow with norepinephrine levels. In fact, a positive and significant correla-
tion between the plasma catestatin level and norepinephrine level was observed in
different myocardial ischemia states. However, in patients plasma catestatin on
admission was not associated with adverse cardiac events. Moreover, there was not
an appreciable relationship between plasma catestatin and onset of new cardiovascu-
lar events (Liu et al. 2014 ). More recently, the cardioprotective effect of CST has
been described. In particular, this peptide seems to be cardioprotective when added
Cardioprotection and Chromogranin A-Derived Peptides