Enhancement of the citrulline-nitric oxide cycle in astroglioma cells by the proline-rich peptide-10c from Bothrops jararaca venom.
The biological activity of the proline-rich decapeptide Bj-PRO-10c, a processing product of the C-type natriuretic peptide precursor protein, expressed in the brain and the venom gland of the pit viper Bothrops jararaca, was originally attributed to the inhibition of the somatic angiotensin-converting enzyme activity with subsequent anti-hypertensive effect. However, recent results suggest broader biological activity may also be involved in the cardiovascular effects of this peptide. Here we show that Bj-PRO-10c enhances and sustains the generation of nitric oxide (NO) by regulating argininosuccinate synthase activity and thereby velocity of the citrulline-NO cycle. Bj-PRO-10c-mediated effects not restricted to the cardiovascular system, since NO production was also induced in cells of astroglial origin. Bj-PRO-10c was internalized by C6 astroglioma cells where it induces NO production and upregulation of the citrulline-NO cycle cells in a dose-dependent fashion. In view of that, astroglial cells function as L-arginine pool for NO production in neighboring neurons, we suggest a regulatory function for Bj-PRO-10c on the metabolism of this gaseous neurotransmitter in the CNS. Moreover, proliferation of astroglial cells was reduced in the presence of Bj-PRO-10c; however, cell death was not induced. Since NO donors have been studied for the treatment of solid cancers, Bj-PRO-10c may serve as structural model for developing drugs to improve the effects of cancer therapy based on the peptide's ability to augment NO production.
de Oliveira
Eduardo Fontana
EF
Center for Applied Toxinology - CAT-CEPID, Instituto Butantan, SP, Brazil.
Guerreiro
Juliano R
JR
Silva
Carlos A
CA
Benedetti
Gabriel Fernando de Souza
GF
Lebrun
Ivo
I
Ulrich
Henning
H
Lameu
Claudiana
C
Camargo
Antonio C M
AC
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001123:Argininosuccinate Lyase / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000378:metabolism; D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002956:Citrulline / Q000378:metabolism*; D003435:Crotalid Venoms / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D055232:Proline-Rich Protein Domains / Q000502:physiology; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects
D003435:Crotalid Venoms; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase