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2.1 Cardiac Properties of the Vasostatin-Derived
Chromofungin
Within the VS-1 domain, a cardiovascular function was recently described for the
fragment 47–66. It was identified by Lugardon and collegues in 2001 , and named
chromofungin (Chr) for its antifungal activity, was identified by Lugardon and col-
legues (Lugardon et al. 2001 ). This fragment generates during infections by cleav-
age by Staphylococcus aureus protease Glu-C (Metz-Boutigue et al. 1993 ). It acts
as an immediate protective shield against pathogens (Metz-Boutigue et al. 1998 ),
being able to inhibit microbial cell metabolism (Bartizal et al. 1992 ), and to pene-
trate the cell membrane, thus inducing extracellular Ca2+ entry by a CaM-regulated
iPLA2 pathway (Zhang et al. 2009 ). According to data found on the in vitro isolated
working heart of the frog Rana esculenta, Chr also possesses cardioactive proper-
ties (Tota et al. 2003 ; for details, see Gattuso, Imbrogno, Mazza, Chap. 9 , present
volume). In fact, the Chr sequence was found to depress frog myocardial contractil-
ity by eliciting a direct negative inotropic effect (Tota et al. 2003 ). Very recently, Chr
cardiovascular actions were extended also to mammals. By using the isolated and
Langendorff perfused rat heart, Filice and co-workers ( 2015 ) investigated the influ-
ence elicited by Chr on the basal cardiac performance and in the presence of myo-
cardial I/R damage. Data showed that exogenous Chr directly affects the heart by
dose-dependently reducing contractility under unstimulated conditions. It reduces
LVP, and (LVdP/dt)max (indexes of inotropism), without affecting HR and
CP. These effects are obtained by Chr concentrations close to the physiological
range of the precursor, CgA, in human serum (Helle et al. 2007 ). With respect to the
data reported on the frog heart (Tota et al. 2003 ), Filice et al. ( 2015 ) demonstrated
in the rat that Chr depresses not only contractility (~40% rat vs ~18% in frog), but
also relaxation without changing heart rate. It in fact reduces two lusitropic indexes,
(LVdP/dt)min and T/-t. Negative inotropic and lusitropic effects induced by Chr
(~40%) resemble the cardiodepression elicited on the rat heart by human recombi-
nant (hrCgA1-78) (~20%) which includes the Chr sequence (Cerra et al. 2006 ). This
further stresses the depressive myocardial properties of the CgA N-terminal domain.
However, Chr did not change rat coronary reactivity. Although VSs and Chr elicit
similar effects on myocardial contractility and relaxation, sequence-specific vascu-
lar activities may account for the observed differences in coronary responses. Of
note, a strong structure-function relationship characterizes CgA-derived peptides,
suggesting that different fragments may display different cardioactivity.
As in the case of the other N-terminal CgA fragments, the presence of receptor-
ligand interactions which mediate the cardiac effects of Chr remains elusive. Of
note, Metz-Boutigue et al. ( 2003 ) reported that Chr exerts antibacterial and anti-
funginal effects by penetrating into, or interacting with, the cell membrane through
hydrophobic interactions between specific domains of the peptides and spatially
localized regions of the lipid bilayer with consequent modulation of cellular effec-
tors. In particular, an increase of peptide penetration is observed for the presence of
ergosterol, the main sterol in yeast and fungus plasma membrane (Metz-Boutigue
et al. 2003 ).
T. Angelone et al.