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same as those involved in preconditioning (for reviews see Hausenloy et al. 2011 ;
Kaur et al. 2009 ; Lacerda et al. 2009 ; Pagliaro and Penna 2015 ; Philipp et al. 2006 ;
Tullio et al. 2013 ; Vinten-Johansen et al. 2011 ).
The RISK pathway comprises the activation of several enzymes, such as PI3K- Akt
and MEK-ERK-1/2 as above described. Also, the end point are mitochondria and
sarcoplasmic reticulum which in concert limit cytoplasmic and mitochondrial Ca+2
overload, thus limiting cell damages. Subsequently, the attention of researchers was
attracted by STAT3 in SAFE pathway: the deletion of STAT3 abolished the reduction
of infarct size usually observed after PostC maneuvers (Negoro et al. 2000 ). Moreover,
the pharmacological postconditioning was obtained by exogenous tumor necrosis fac-
tor α (TNFα) in wildtype, but not in STAT3 knockout mice (Lacerda et al. 2009 ;
Negoro et al. 2000 ; Tsang et al. 2004 ). Of note, mitochondrial translocation of STAT3
has been observed in these models of PostC and TNFα induced cardioprotection. Of
note, only the mechanical maneuvers of ischemic PostC induced this translocation,
while this mechanism is absent when PostC is induced by Diazoxide (Penna et al.
2013 ). Since Diazoxide acts via a redox- mechanism, these data suggest a redox-inde-
pendent mechanism in the SAFE pathway. Whether or not mitochondrial STAT3 con-
tributes to the cardioprotection by PostC should be confirmed in further studies
(Boengler et al. 2011 ; Lacerda et al. 2009 ).
3 Chromogranin Fragments and Cardioprotection
3.1 Vasostatin 1
It has been reported that the N-terminal CgA-derived Vasostatin 1 (VS-1) counter-
acts the effects of adrenergic stimulation and mediates NO-dependent vasodilation,
acting on both the endothelial and endocardial cells (Cerra et al. 2006 ). VS-1 thus
contributes to protection against excessive excitatory sympathetic changes (Cerra
et al. 2006 , 2008 ; Gallo et al. 2007 ; Ramella et al. 2010 ). We have shown that in the
isolated rat heart VS-1 induces cardioprotection when infused before of I/R: this
protection recapitulates many aspects of IP. We have shown that low concentration
of VS-1 (80 nM), administered before I/R, may activate adenosine/NO/PKC signal-
ing (Cappello et al. 2007 ). In basal condition, VS-1 at 33 nM in isolated rat heart,
induces the reduction of the left ventricular pressure (LVP), the maximal values of
the first derivative of LVP (dP/dtmax) and of the rate-pressure. These effects of VS-1
were abolished blocking the Gi/o proteins/NOS/NO/solubleGC/PKG pathway. These
data demonstrate the involvement of molecular mechanisms in the VS-1- dependent
negative inotropic effects similar to those involved in cardioprotection. In fact, the
infusion of VS-1 before ischemia reduced the infarct size, which was by about 50%
of the risk area. This protection was NO/PKC dependent, in fact it was abolished by
either NOS or PKC inhibition. However, cardioprotection was only attenuated by
C. Penna and P. Pagliaro