Chromogranins from Cell Biology to Physiology and Biomedicine

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Pivotal role is assigned to protein kinase C (PKC) as point of convergence of the
protective triggering pathway. In fact, the opening of mitoKAT P channels and release
of ROS may activate PKC (Oldenburg et al. 2002 , 2004 ) (Fig.  2 ). PKC may also be
directly activated by adenosine via activation of phospholipase C (PLC) mecha-
nism. Activation of PKC and other kinases represent the memory phase.
When these above described pathways are activated, the heart displays a pro-
tected phenotype which persists for a couple of hours even after the triggering auta-
coids have been washed out.
In the mediation phase the adenosine A2b receptors are activated by PKC and
during the reperfusion phase, which follows the infarcting ischemia, these receptors
may be responsible of the re-activation of PKC (Oldenburg et al. 2002 ; Yue et al.
2002 ). The downstream signaling to A2b receptors recapitulates somehow those seen
in the trigger pathway. The final point of these signaling is to prevent the formation
of mPTP (Tissier et  al. 2007 ; Zorov et  al. 2009 ). Several investigations of the
signaling pathways, underlying IP mediation phase, have identified a number of
different signal transduction pathways conveying the cardioprotective signal from
the sarcolemma to the mitochondria, some of which overlap with postconditioning
(see below). These reperfusion signaling pathways include the Reperfusion Injury
Salvage Kinase (RISK) pathway and the more recently described Survivor Activating
Factor Enhancement (SAFE) pathway, two apparently distinct signal cascades

gp130 TNFR2^

PI3K

Akt

eNOS

NO

GC

PKG

cGMP

PKCε (^) ROS
Mek1/2
ERK1/2
p70S6K
GSK3β
Blocking/reducon
Mitochondrial dysfuncon, swelling, rupture
mKATP
Channel
Jak
STAT-3
RISK pathway SAFE pathway
Fig. 2 Scheme depicting the principal factors involved in cardioprotective pathways triggered by
preconditioning. The activation of cellular surface receptors in response to an ischemic condition-
ing stimulus recruits SAFE and RISK pathways. The end-point of these signal transduction path-
ways are the salvage of mitochondrial structure and activity with activation of mitochondria-dependent
protective pathways (Akt Serine/threonine protein kinase, cGMP/PKG Cyclic guanosin mono-
phosphate/protein kinase G, eNOS Endothelial NO synthase, ERK1/2 Extracellular regulated
kinase 1/2, GSK3β Glycogen synthase kinase 3 β, MEK Mitogen-activated protein kinase kinase,
mPTP Mitochondrial permeability transition pore, mitoKATP mitochondrial ATP-dependent K+
channels, NO Nitric oxide, P70S6K p70 ribosomal S6 protein kinase, PLC phospholipase C, PI3K
Phosphoinositide 3-kinase, PKG Protein kinase G, RISK Reperfusion injury salvage kinases, ROS
reactive oxygen species)
Cardioprotection and Chromogranin A-Derived Peptides