Tissue distribution in mice of BPP 10c, a potent proline-rich anti-hypertensive peptide of Bothrops jararaca

Silva, Carlos Antônio da; Portaro, Fernanda Calheta Vieira; Fernandes, Beatriz Lieblich; Ianzer, Danielle; Guerreiro, Juliano R.; Gomes, Claudiana L.; Konno, Katsuhiro; Serrano, Solange M.T.; Nascimento, N.; Camargo, Antônio Carlos Martins de

doi:10.1016/j.toxicon.2007.11.003

Cited by 26 publications

(25 citation statements)

References 26 publications

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“…These results prompted us to speculate whether a different mechanism, not requiring the participation of angiotensin-II and bradykinin, could be implicated in the in vivo activity of Bj-BPP-10c. This hypothesis received support from the tissue distribution studies by Silva et al (7), who showed that 40 -50% of 125 I-Bj-BPP10c remained in the kidneys of mice, even when a 1,000-fold higher molar concentration of captopril was administered with the peptide.…”

Section: Discussionmentioning

confidence: 88%

“…This result led us to hypothesize that, besides sACE, another molecule involved in the arterial blood pressure homeostasis could possibly be a target for Bj-BPP-10c. Two reasons prompted us to search the putative target in the kidney: (i) the crucial role played by the kidney in the arterial blood pressure control (6) and (ii) the selective concentration and long lasting permanence of 125 I-Bj-BPP-10c in the mouse kidney even when a saturating concentration of captopril was administered with the peptide (7).…”

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confidence: 99%

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Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide

Guerreiro

Lameu

Oliveira

et al. 2009

Journal of Biological Chemistry

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Bj-BPP-10c is a bioactive proline-rich decapeptide, part of the C-type natriuretic peptide precursor, expressed in the brain and in the venom gland of Bothrops jararaca. We recently showed that Bj-BPP-10c displays a strong, sustained anti-hypertensive effect in spontaneous hypertensive rats (SHR), without causing any effect in normotensive rats, by a pharmacological effect independent of angiotensin-converting enzyme inhibition. Therefore, we hypothesized that another mechanism should be involved in the peptide activity. Here we used affinity chromatography to search for kidney cytosolic proteins with affinity for Bj-BPP-10c and demonstrate that argininosuccinate synthetase (AsS) is the major protein binding to the peptide. More importantly, this interaction activates the catalytic activity of AsS in a dose-dependent manner. AsS is recognized as an important player of the citrulline-NO cycle that represents a potential limiting step in NO synthesis. Accordingly, the functional interaction of Bj-BPP-10c and AsS was evidenced by the following effects promoted by the peptide: (i) increase of NO metabolite production in human umbilical vein endothelial cell culture and of arginine in human embryonic kidney cells and (ii) increase of arginine plasma concentration in SHR. Moreover, ␣-methyl-DL-aspartic acid, a specific AsS inhibitor, significantly reduced the anti-hypertensive activity of Bj-BPP-10c in SHR. Taken together, these results suggest that AsS plays a role in the anti-hypertensive action of Bj-BPP-10c. Therefore, we propose the activation of AsS as a new mechanism for the anti-hypertensive effect of Bj-BPP-10c in SHR and AsS as a novel target for the therapy of hypertension-related diseases.Inhibition of somatic angiotensin-I-converting enzyme (sACE) 3 is a widely used approach in the treatment of hypertension. The first available competitive inhibitors of sACE were the naturally occurring proline-rich oligopeptides from the venom of Bothrops jararaca. Clinical studies using Bj-BPP-9a, teprotide, the most efficient of these snake venom peptides, demonstrated the potential of sACE inhibitors as anti-hypertensive drugs (1). Highly potent inhibitors of sACE, which can be administered orally, have subsequently been developed. The first of these, captopril, was designed employing a theoretical model of the active site of sACE, based on its presumed similarity to the active site of carboxypeptidase A and also with reference to the C terminus of venom proline-rich peptides, which compete with sACE substrates (2). Since captopril reproduced all known pharmacological effects and sACE-inhibiting features of the proline-rich peptides (3), the interest to deepen the investigation of the biological properties of these naturally occurring sACE inhibitors dropped dramatically. However, we recently showed that the Bj-BPP-10c (ϽENWPHPQIPP, where ϽE represents pyroglutamic acid), the most selective inhibitor of the active site at the C-domain of sACE (4), displays a strong and sustained anti-hypertensive effect in spontaneo...

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide

Guerreiro

Lameu

Oliveira

et al. 2009

Journal of Biological Chemistry

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“…Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel estrogen receptor coactivator that plays an important role in the genomic and nongenomic actions of estrogen receptors [19]. A proline-rich peptide with antihypertensive effect was found in snake venom [20]. Peptides derived from lamellipodin play a role in the organization of butylcholinesterase subunits into a tetramer [21].…”

Section: The Proline-rich Peptide Familymentioning

confidence: 99%

Colostral Proline-Rich Polypeptides – Immunoregulatory Properties and Prospects of Therapeutic Use in Alzheimers Disease

Janusz¹,

Zabłocka

2010

CAR

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A proline-rich polypeptide complex (PRP), subsequently called Colostrinin(CLN), was first isolated from ovine colostrum, was shown to possess immunoregulatory properties, including effects on the maturation and differentiation of murine thymocytes and humoral and cellular immune responses, both in vivo and in vitro. PRP seems to restore balance in cellular immune functions and is not species specific. PRP is a complex of peptides of molecular masses ranging from 500 to 3000 Da. The polypeptide contains 25% proline and 40% hydrophobic amino acids. PRP shows a regulatory activity in cytokine (IFN, TNF-alpha, IL-6, IL-10) induction and possesses the ability to inhibit the overproduction of oxygen reactive species and nitric oxide. Besides its immunoregulatory activity, PRP also showed psychotropic properties, improving cognitive activity and behavior of old rats, humans, and chickens. The properties of PRP prompted the authors to propose the complex for the treatment neurodegenerative disorders. Beneficial effects of PRP/Colostrinin were shown for the first time in double-blind placebo-controlled trials and long-term open-label studies. The results were confirmed in multicenter clinical trials. A very important property of PRP/Colostrinin is the prevention of Abeta aggregation and the disruption of already existing aggregates. The same properties were expressed by one of PRP's components, a nonapeptide (NP). Moreover, PRP modulates neurite outgrowth, suppresses uncontrolled activation of cells, reduces 4-HNE-mediated cellular damage, and modulates expression in cellular redox regulation, cell proliferation, and differentiation. Its biological response modifying activity can play an important role in its use in the treatment of Alzheimer's disease.

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“…Several studies recently demonstrated that carnosine (b-AlaHis) presented antihypertensive, antioxidative and neuroprotective properties [37][38][39]. Moreover, it was demonstrated that the N-acetylation of carnosine improves its antioxydative potential [1].…”

Section: Enzymatic Acylation Of a Bioactive Dipeptide: Carnosinementioning

confidence: 99%

Enzymatic acylation of polar dipeptides: Influence of reaction media and molecular environment of functional groups

Husson

Humeau²,

Paris³

et al. 2009

Process Biochemistry

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Tissue distribution in mice of BPP 10c, a potent proline-rich anti-hypertensive peptide of Bothrops jararaca

Cited by 26 publications

References 26 publications

Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide

Argininosuccinate Synthetase Is a Functional Target for a Snake Venom Anti-hypertensive Peptide

Colostral Proline-Rich Polypeptides – Immunoregulatory Properties and Prospects of Therapeutic Use in Alzheimers Disease

Enzymatic acylation of polar dipeptides: Influence of reaction media and molecular environment of functional groups

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