title: Enhancement of the citrulline-nitric oxide cycle in astroglioma cells by the proline-rich peptide-10c from Bothrops jararaca venom.
abstract: 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.
authors.affiliation: Center for Applied Toxinology - CAT-CEPID, Instituto Butantan, SP, Brazil.
authors.forename: Eduardo Fontana
authors.initials: EF
authors.lastname: de Oliveira
authors.forename: Juliano R
authors.initials: JR
authors.lastname: Guerreiro
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Silva
authors.forename: Gabriel Fernando de Souza
authors.initials: GF
authors.lastname: Benedetti
authors.forename: Ivo
authors.initials: I
authors.lastname: Lebrun
authors.forename: Henning
authors.initials: H
authors.lastname: Ulrich
authors.forename: Claudiana
authors.initials: C
authors.lastname: Lameu
authors.forename: Antonio C M
authors.initials: AC
authors.lastname: Camargo
mesh_terms: 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
chemical_list: D003435:Crotalid Venoms; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase