121The study by Filice et al. ( 2015 ) revealed that, as full length CgA (Pasqua et al.
2013 , see for details Tota, Cerra, Chap. 7 , present volume), VSs and CST (Cappello
et al. 2007 ; Angelone et al. 2008 ), the cardiac effects induced by Chr involve the
AkT/NOS-NO/cGMP signal transduction pathway. On the rat heart, exposure to
Chr increased AkT and eNOS phosphorylation, thus activating the NO-generating
cascade. This promotes cGMP production by soluble Guanylate Cyclase (sGC),
with final depressant effects on contractility and relaxation (Fig. 3 ).
Of relevance, Chr also protects the myocardium against I/R injury, acting as a
Post conditioning agent (Filice et al. 2015 ). Given in the early reperfusion, the pep-
tide limits the I/R-dependent myocardial damage. This protection, similar to that
obtained by ischemic Post conditioning maneuvers (Vinten-Johansen et al. 2005 ), is
indicated by a significant reduction of infarct size and LDH release. Ischemic hearts
exposed to Chr (75 nM) also show a marked improvement of the post-ischemic
contractile function expressed as a decrease of contracture development, which is
the goal of cardioprotective protocols, due to its inverse relation with the I/R- -
dependent myocardial damage (Penna et al. 2008 ). In line with the observed cardio-
protection, the inhibition of the PI3K and ERK1/2, upstream kinases of the protective
RISK cascade, abolished the systolic recovery induced by Chr. During reperfusion,
both PI3K-Akt and ERK1/2 are activated and converge on GSK3β, inducing its
phosphorylation/inactivation with a final control on mitoKATP channels, one of the
terminal elements of Post conditioning protection (Gomez et al. 2008 ). Of note,
inhibition of mitoKAT P channels abolished myocardial cardioprotective induced by
Chr (Filice et al. 2015 ). Chr-dependent cardioprotection is accompanied by increase
of intracellular cGMP, an effect which disappears in hearts co-treated with ODQ,
specific GC inhibitor. The importance of cGMP in cardioprotection is well known
(Penna et al. 2006 ). In fact, Post conditioning depends on GC activation via either
NOS-dependent or NOS-independent pathways (Penna et al. 2006 , 2008 ).
Lastly, Chr-dependent cardioprotection is accompanied by an increased miRNA-
21 expression. This is of relevance since miRNA are small noncoding RNAs that
mediate post-transcriptional gene silencing, involved in cardiac physiopathology.
Their deregulated expression is linked to the developement of cardiovascular disor-
ders, including infarct size (Zhang 2008 ; Dong et al. 2009 ).
3 Cardiac Actions of Catestatin
The CgA352-372 fragment CST, known as a potent endogenous inhibitor of nico-
tinic receptor (nAChR)-evoked CA secretion (Mahata et al. 1997 ), is a multifunc-
tional peptide with multiple targets and a relevant vasoactive and anti-hypertensive
properties (for ref. Mahata et al. 2010 ). In mammals, it is present as both wild type
peptide (WT-CST, human CgA352-372) and naturally occurring variants (G364S-
CST and P370L-CST). As shown on the ex vivo isolated and Langendorff perfused
rat heart, wild-type CST, G364S-CST, and P370L-CST affect heart function, also in
the absence of the control exerted by SAN over cardiac output (CO) and vascular
Cardiac Physio-Pharmacological Aspects of Three Chromogranin A-Derived Peptides...