155negative inotropic effects, while coronary pressure was unaffected. The negative
effect of Chr was mediated by the AKT/eNOS/cGMP/PKG pathway. These results
suggest that, among CgA-derived peptides, also Chr may considered as a new phys-
iological neuroendocrine modulator of cardiac function.
2.4 Serpinin
Recent data suggest that serpinin peptides act as novel β-adrenergic-like cardiac
modulators (Tota et al. 2012 ). Three forms of serpinin peptides, serpinin (Ala26Leu),
pyroglutaminated (pGlu)-serpinin (pGlu23Leu) and serpinin-Arg-Arg-Gly
(Ala29Gly) derive from cleavage at pairs of basic residues in the highly conserved
C terminus of CgA. Serpinin and pGlu-serpinin exert dose-dependent positive ino-
tropic and lusitropic effects, while Ala29Gly was unable to affect myocardial per-
formance. Moreover, pGlu-serpinin was able to induce positive inotropism also on
the isolated rat papillary muscle preparation. Both pGlu-serpinin and serpinin act
through a β1-AR/AC/cAMP/PKA pathway, indicating that, contrary to the
β-blocking profile of the other CgA-derived cardiosuppressive peptides, VS-1, CST
and Chr, these two C-terminal peptides act as β-adrenergic-like agonists, suggesting
that CgA derived peptides can play a key role on the modulation of myocardial
performance.
Taken together, the experiments performed on isolated perfused hearts of differ-
ent animal species (amphibian, fish and mammal) as well as on isolated rat papillary
muscle, suggested a long evolutionary history of CgA-derived peptides as cardiotro-
pic agents. In particular, while VS-1, CST and Chr displayed negative inotropic and
lusitropic effects, opposing to β-adrenergic stimulation, Serpinin and pGlu-serpinin
were able to potentiate cardiac performance, eliciting positive inotropic and lusi-
tropic effects. In general, apart from their species-specific mechanisms of action,
the negative effects of VS-1, CST and Chr appear to be mediated by endocardial/
vascular endothelial cells, and activation of the AKT/eNOS/cGMP/PKG pathway.
In contrast, the cardio-stimulatory action of Serpinin and pGlu-serpinin requires a
β1-adrenergic receptor/adenylate cyclase/cAMP/PKA pathway. As suggested by
Angelone et al. (2012a), all these so far obtained findings indicate that “the pro-
hormone CgA appears to possess two cardioactive limbs, i.e. an inhibitory
N-terminal region and a C-terminal stimulatory domain. These two limbs may func-
tion according to a ying/yang strategy whose spatial and temporal traits remain the
goal for future research.”
The main effects exerted by CgA derived peptides on cardiac function and related
pathways are summarized in Table 1.
Signalling Pathways of CgA-Derived Peptides in Cardiac and endothelial cells