16 4
cardio-suppressive and vasodilator properties of VS-1 and CST have been recently
explained as due to a PI3K-dependent-NO release by endothelial cells. At present,
the signalling pathways involved in the cardiovascular responses to VS-I and CST
are only fragmentary. As typical high-affinity receptors have not been identified, the
cellular processes upstream the eNOS activation exerted by these peptides are still
partially unknown. In recent works performed in our laboratory, we showed that, in
endothelial cells, on the basis of their cationic and amphipathic properties, both
VS-1 and CST act as cell penetrating peptides, binding to heparan sulfate proteogly-
cans and activating eNOS phosphorylation through a PI3K-dependent, endocytosis-
coupled mechanism. These results suggest a novel signal transduction pathway for
endogenous cationic and amphipathic peptides in endothelial cells: HSPGs interac-
tion and caveolae endocytosis, coupled with a PI3K-dependent eNOS phosphoryla-
tion. Besides to be advantageous to an organism under stress, being able to reduce
the adrenergic signal response and to cause a vasodilatatory effect, both VS-1 and
CST exert a protective effect against cell death and cardiac alterations induced by
ischemia and reperfusion. Interestingly, CST is able to promote cardiomyocyte sur-
vival also in the case of isolated ventricular cells undergoing simulated I/R. This
effect is attained at a very low concentration, comparable to the circulating concen-
trations of this peptide found in healthy humans. These results reopen the question
concerning the presence of specific receptors for CTS on cardiac cells, suggesting
that CST is able to attain such protection also via a direct effect on cardiomyocytes,
independent from endothelial cells. In conclusion, CgA-derived peptides, in par-
ticular CST, are emerging as very important mediators regulating cardiovascular
functions in stress situations, and bear all the potentials to be therapeutic agents to
treat several diseases affecting the cardiovascular system, like hypertension or isch-
emic heart disease.
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