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sympatho- adrenal tone and cardiovascular functions. Importantly, CST, VS-1 and
Serp also act as cardioprotective agents against ischemia/reperfusion injury in both
pre- and post-conditioning mechanisms, through specific effects, which include
NO-dependent mechanisms, the activation of Reperfusion Injury Salvage Kinase
signaling and the modulation of mitochondrial activity (Cappello et al. 2007 ; Penna
et al. 2010a, b, 2014 ; Perrelli et al. 2013 ). In this chapter, we describe the studies
that elucidated the cardioprotective role of CgA derivatives.
Before proceeding with this description, we treat briefly some aspects of cardiac
ischemia/reperfusion (I/R) damage. Indeed, in different animal models the levels of
CgA and CgA derivatives were evaluated in the presence of I/R and have been sug-
gested as independent predictors of mortality after acute myocardial infarction. For
example, in pigs after 1 h of regional myocardial ischemia followed by 3 h of reper-
fusion, the plasma level of N-terminal CgA (VS-1) revealed a 30% increase 1 h after
the re-establishment of coronary perfusion, whereas the level of pancreastatin,
another CgA fragment, did not increase in response to I/R, but decreased during the
entire experiment. These results suggest a differentiated CgA processing in myocar-
dial I/R and can reflect tissue-specific post-translational modifications and release
of these peptides (Frydland et al. 2013 ).
We now consider the ischemia/reperfusion injury, the cardioprotective strategies
and pathways and, finally, the cardioprotective effects of CgA derived peptides.
2 Ischemia/Reperfusion Injury and Cardioprotective
Strategies: Preconditioning and PostConditioning (Fig. 1 )
2.1 Ischemia/Reperfusion Injury
Ischemic heart disease is one of the leading causes of death in the industrialized
countries. The only way to treat coronary occlusion leading to acute myocardial
infarction (AMI) is based on rapid restoration of blood flow to the ischemic zone,
i.e., reperfusion therapy. The rapid reperfusion, however, has the potential to induce
additional lethal injury, in fact it may lead to further myocardial cell death, termed
lethal myocardial reperfusion injury (Jordan et al. 1999 ; Pagliaro et al. 2011 ; Piper
et al. 2003 ). Complex biochemical and mechanical mechanisms are involved in the
reperfusion injury.
In the myocardium, reperfusion injury includes cellular death, which can occur
for different types of death (e.g. necrosis, autophagy and apoptosis). It has been
proposed that necrosis can be caused mainly by ischemia as well as by reperfusion,
whereas the apoptosis is typically induced by reperfusion (Zhao and Vinten-
Johansen 2002 ). Autophagy may be both deleterious and beneficial, depending on a
number of circumstances (for review see Gottlieb et al. 2009 ). Reperfusion injury
also includes myocardial stunning, endothelial dysfunction and no-reflow phenom-
enon (Pagliaro et al. 2011 ).
C. Penna and P. Pagliaro