175besides the release of pro-apoptotic factors, comports disruption of mitochondria
(mitochondrial swelling) and consequently cell death for necrosis or for apoptosis. In
fact, the formation of mPTPs abolishes the electrochemical gradients between the cyto-
plasm and mitochondrial matrix and consequently blocks ATP production, thus deter-
mining cell necrosis. The release of cytochrome c will be the major responsible of cell
apoptosis. It is, thus, likely that in reperfusion the majority of cells die by means of
these two processes (Halestrap 2006 , 2009 ; Juhaszova et al. 2009 ; Zorov et al. 2009 ).
In the reperfusion, the activation of NFκB is also possible. This activation may
be induced by several agents, including ROS/RNS. When activated, NFκB contrib-
utes to the exacerbation of the myocardium injury by sustaining inflammatory pro-
cesses, and determining an upregulation of the genes involved in the production of
cell adhesion molecules (Baldwin and Thurston 2001 ; Lefer and Lefer 1996 ;
Marczin et al. 2003 ; Schreck et al. 1992 ). These molecules may favor the adhesion
of leukocytes to the endothelium and then infiltration into the myocardial wall
(Baldwin and Thurston 2001 ). Therefore, during reperfusion neutrophils are the
main source of ROS (Jordan et al. 1999 ). This production together with the deficient
production of NO induced by I/R, may favor a vicious cycle leading to the activa-
tion/transcription of genes for the production of further cell adhesion molecules
(Beauchamp et al. 1999 ; Lefer and Lefer 1996 ).
The deficit of NO causes vasoconstriction and formation of micro-thrombi in
small vessels (Radomski et al. 1987 ; Schulz et al. 2004 ). These mechanisms, com-
bined with the adhesion of leucocytes to the endothelium, can lead to the so-called
“no-reflow phenomenon” (Reffelmann and Kloner 2002 ). Other pathological mani-
festations of I/R injury induced by oxidative stress are represented by arrhythmias
and myocardial stunning. In fact, increased ROS production and depletion of energy
may also contribute to alterations in excitation-contraction coupling, thus sustaining
myocardial stunning and arrhythmias (Pagliaro et al. 2011 ; Penna et al. 2008 ;
Vinten-Johansen et al. 2011 ).
In summary, reperfusion injury is due to several mechanisms in which mPTP
play a central role being primed by ischemia and opening upon reperfusion, because
of the sudden recovery of pH and simultaneous presence of several damaging fac-
tors, such as Ca2+ overload, ROS generation, and reduced NO bioavailability. All
these factors contribute to the activation of NFκB, which leads to the augmented
expression of cellular adhesion molecules, leukocyte infiltration and no-reflow phe-
nomenon. Therefore, necrotic and apoptotic cell death contributes to reperfusion-
injury which is exacerbated by inflammatory processes (see Fig. 1 ).
2.2 Ischemic Preconditioning
Murry et al. ( 1986 , 1991 ) described in 1986 the ischemic preconditioning (IP) phe-
nomenon. In this groundbreaking study the cardioprotective maneuvers consisted in
4 cycles of 5-min ischemia/5-min reperfusion just prior to a 40-min coronary occlu-
sion. This protocol in dogs induced a marked (75%) reduction of infarct size. Thus,
Cardioprotection and Chromogranin A-Derived Peptides