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the key role of endothelial cells in mediating the myocardial actions of CgA-derived
peptides. In view of the anti-adrenergic effect of NO, CgA presumably exerts a
protective effect on the myocardium, preventing excessive work in stressful
conditions.
4.3 Basic Fibroblast Growth Factor
CST induced migration, proliferation and antiapoptotic effect in endothelial cells,
and promoted capillary tube formation in vitro in a matrigel assay; all these effects
were mediated through the activation PI3K/Akt pathway. The blockade of CST
effects by a neutralizing Basic fibroblast growth factor (bFGF) antibody and the
ability of this peptide to induce bFGF release strongly suggest that CST regulates
endothelial cells functions by stimulating fibroblast growth factor signalling (Teurl
et al. 2010 ).
5 The Cardioprotective Effect of CST on Isolated
Cardiomyocytes Suggests a Direct Cardiac Effect
Recent data suggest that CgA-derived peptides may exert important protective
effect on the heart undergoing ischemia and reperfusion (I/R). Indeed, infusion of
VS-1 before ischemia significantly reduced the development of infarct size and con-
tractile alterations during the reperfusion in the isolated rat heart (Cappello et al.
2007 ). The protective effect of VS-1 was abolished by either NOS inhibition or PKC
blockade and was attenuated, but not suppressed, by the blockade of Adenosine (A 1 )
receptors, suggesting that VS-1 may trigger two different pathways, the first one
mediated by A 1 receptors activation, and the other by NO release. Moreover, Yu
et al. ( 2011 ) recently showed that overexpression of VS-1 in neonatal cardiomyo-
cytes could limit I/R injury, with a mechanism independent from endothelial cells.
Data regarding the ability of CST to induce cardioprotection are, at present, con-
flicting. As shown by Brar et al. ( 2010 ), both the wild type and Pro^370 Leu variants
increased infarct size and decreased the cardiac levels of phosphorylated Akt and
two of its downstream targets, FoxO1 and BAD, when these agents were adminis-
tered during reperfusion in the Langendorff perfused rat hearts subjected to regional
ischemia. However, no significant alteration was present when reperfusion occurred
in the presence of the Gly^364 Ser variant.
In contrast with these findings, it has been also shown that CST induced a cardio-
protective effect when infused only in the early phases of reperfusion, thus simulat-
ing a post-conditioning effect (Penna et al. 2010 ; Perrelli et al. 2013 ). In these
conditions, indeed, CST limited the extension of infarct size, reduced post-ischemic
development of diastolic contracture, and significantly improved post-ischemic
recovery of developed left ventricular pressure during reperfusion. These results
G. Alloatti and M.P. Gallo