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which may actually interact to mediate IP and Postconditioning (PostC)
cardioprotection (Philipp et al. 2006 ; Lecour 2009 ) (Fig. 2 ).
The fundamental role of activation of Akt in the cardioprotection, has been dem-
onstrated by numerous studies. The cardioprotective effect induce by Akt activation
is correlated to signaling mediated G protein–coupled receptors (Kuno et al. 2008 ;
Means et al. 2008 ; Perrelli et al. 2011 ; Sarbassov et al. 2005 ), receptors of tyrosine
kinases and glycoprotein 130–linked receptors (Fujio et al. 2000 ; Hausenloy et al.
2011 ). The activation of these receptors induces the PI3K system activation with an
increase of phosphatidylinositol triphosphate (PIP3) levels (Fujio et al. 2000 ;
Hausenloy et al. 2011 ; Matsui et al. 1999 ). The translocation of Akt to the plasma
membrane is favored by PIP3. Activation/phosphorylation of Akt occurs through
phosphorylation at Thr308 by phosphoinositide-dependent kinase 1 (PDK1) and
through phosphorylation at Ser473 via both TORC2 mechanism and the intrinsic
catalytic activity of Akt (Craig et al. 2001 ; Miyamoto et al. 2008 ; Negoro et al. 2001 ).
Recently Goodman et al. ( 2008 ) and Gross et al. ( 2006 ) reported the possibility that
Akt is also phosphorylated by signal transducer and activator of transcription 3
(STAT3) or Janus Kinase (JAK). It is well known that STAT3 leads to changes in
gene transcription, transducing stress signals from the plasma membrane to the
nucleus. The cardiac role of STAT3 is very intriguingly, in fact it is involved in hyper-
trophy and apoptosis and development of infarct size after I/R protocol. In addition,
it has been recently reported that STAT3 plays a cardioprotective role in the SAFE
pathway which includes JAK/STAT signal transduction (Newton 2003 ; Sarbassov
et al. 2005 ). In particular, during cardioprotective protocols, STAT3 has been local-
ized with molecular biology and confocal laser scan microscopy in isolated mito-
chondria (Boengler et al. 2008a; Goodman et al. 2008 ; Gross et al. 2006 ). During
ischemia/reperfusion STAT3 is activated by phosphorylation (Lacerda et al. 2009 ;
Wegrzyn et al. 2009 ), different cardioprotective maneuvers induce its phosphoryla-
tion/activation (Boengler et al. 2010 , 2011 ; Fuglesteg et al. 2008 ; Gross et al. 2006 ;
McCormick et al. 2006 ; Negoro et al. 2000 ), with reduction of cardiomyocyte death
and adverse cardiac remodeling after I/R injury (Kelly et al. 2010 ). Both IP and
PostC comprises STAT3 phosphorylation with closure of mPTP (Boengler et al.
2008a, b; Goodman et al. 2008 ; Lecour et al. 2005 ; Sarbassov et al. 2005 ).
Other important IP mechanism is dependent on NO/nitroxyl (HNO) effects
(Pagliaro 2003 ; Penna et al. 2008 ). NO-dependent, PKG-independent mechanism is
also described (Inserte and Garcia-Dorado 2015 ; Penna et al. 2008 ). The latter
includes the intervention of ONOO− and other RNS, which in concert with ROS can
activate PKC (Cohen and Downey 2008 ). NO/cGMP/PKG signaling is cardiopro-
tective also in PostC (see below).
The activation of adenosine receptors induces the activation of PKC, and this
pathway is independent of the NO/cGMP pathway (Yang et al. 2010 ), but, as said,
PKC can also be activated via the activation of a NO-cGMP-PKG pathway (Lacerda
et al. 2009 ; Pagliaro et al. 2003 ; Simkhovich et al. 2013 ). Therefore, adenosine may
have much more direct and strong coupling to PKC (Lacerda et al. 2009 ; Cohen and
Downey 2011 ; Cohen et al. 2000 , 2006 ; Penna et al. 2005 ; Peart and Gross 2003 ).
C. Penna and P. Pagliaro