125This is of paramount importance in disease states characterized by LV diastolic
dysfunction, including LV hypertrophy and chronic HF. In the failing heart of aged
SHR, characterized by contractile and relaxing alteration (Han et al. 2014 ) the
mechanisms for NO generation are impaired because of a dysfunctional endothe-
lium, and a decreased expression of eNOS (Bayraktutan et al. 1998 ; Zhang et al.
2008 ). Under these circumstances, a reduced NO availability, and the consequent
limitation of myocardial coronary perfusion, elicits detrimental effects on the
hemodynamic performance (Bayraktutan et al. 1998 ).
It is known that NO mediates the inotropic response to sustained stretch through
a mechanism that involves S-Nitrosylation of target proteins that include G protein-
coupled receptors, Hsp90 (a chaperone involved in eNOS activation), mitochondrial
pro-apoptotic and anti-apoptotic proteins (see for references Angelone et al. 2015 ).
Notably, S-Nitrosylation also occurs on SR RyR channels, potassium channels, and
L-type calcium channels, with important influences on calcium cycling and contrac-
tility (see for references Angelone et al. 2015 ). In the heart of both WKY and SHR,
CST increases NO-dependent S-Nitrosylation mainly of high and low molecular
weight proteins. In particular, an augmented S-Nitrosylation is observed at 100 kDa.
This corresponds to the apparent molecular weight of dynamin, a GTPase which
can be S-Nitrosylated by NO and is emerging in the heart as a regulator of traffick-
ing and function of ion channels, including L-type calcium channels (Angelone
et al. 2015 ).
Of note, CST-induced effect on the Frank-Starling behavior is of the same mag-
nitude as that induced by NO. This supports the notion that this CgA fragment, also
in the case of the humoral regulation of the ventricular heterometric response, func-
tions as endogenous NOS activator. In the presence of a deteriorated function, as in
the failing heart of aged SHR, this CST-dependent NO production may represent an
advantage to the diseased heart since it counteracts the cardiac damage induced by
hypertension.
4 Cardiac Actions of Serpinin
CgA cleavage at the penultimate and the last pair of basic residues at C-terminus
(CgA403-428) generates a short fragment called Serp (Koshimizu et al. 2010 ,
2011a). It was described for the first time in mouse pituitary cell line (AtT-20) in
which stimulates granules biogenesis (Kim and Loh, 2006 ). More recently, HPLC
and ELISA techniques revealed the presence of Serp peptides in the mammalian
(rat) heart (Tota et al. 2012 ). Three naturally occurring Serp peptides are expressed
by the rat cardiac tissue, namely Serp (Ala26Leu), and the two predominant frag-
ments: pyroglutaminated Serp (pGlu-Serp) and a C-terminal extended form, Serp-
Ala29Gly (Tota et al. 2012 ). This suggests that the rodent heart is able to process the
C terminal domain of CgA, as it does with the N terminal domain. Exposure of the
Langendorff perfused rat heart showed that Serp peptides modulate cardiac perfor-
mance but, different from the cardiodepressive VS-1 and CST, they stimulate the
Cardiac Physio-Pharmacological Aspects of Three Chromogranin A-Derived Peptides...