Crambescin C1 Acts as A Possible Substrate of iNOS and eNOS Increasing Nitric Oxide Production and Inducing In Vivo Hypotensive Effect.

Autor:	Rubiolo JA; Departamento de Zoología, Genética y Antropología Física, Universidad de Santiago de Compostela, Lugo, Spain.; Facultad de Ciencias Bioquímicas y Farmacéuticas-Ministerio de Ciencia, Centro Científico y Tecnológico Acuario del Río Paraná, Tecnología e Innovación Productiva de Santa Fe, Universidad Nacional de Rosario, Rosario, Argentina., Lence E; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, Santiago de Compostela, Spain., González-Bello C; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, Santiago de Compostela, Spain., Roel M; Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain., Gil-Longo J; Departamento de Farmacología, Facultad de Farmacia, Farmacia y Tecnología Farmacéutica, Universidad de Santiago de Compostela, Santiago de Compostela, Spain., Campos-Toimil M; Departamento de Farmacología, Facultad de Farmacia, Farmacia y Tecnología Farmacéutica, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.; Fisiología y Farmacología de las Enfermedades Crónicas (FIFAEC), CIMUS, Universidad de Santiago de Compostela, Santiago de Compostela, Spain., Ternon E; CNRS, OCA, IRD, Géoazur, Université Côte d'Azur, Valbonne, France., Thomas OP; Marine Biodiscovery, School of Chemistry and Ryan Institute, National University of Ireland Galway, Galway, Ireland., González-Cantalapiedra A; Departamento de Anatomía, Producción Animal y Ciencias Clínicas Veterinarias, Hospital Veterinario Universitario Rof Codina, Facultad de Veterinaria, Universidad de Santiago de Compostel, Lugo, Spain., López-Alonso H; Departamento de Anatomía, Producción Animal y Ciencias Clínicas Veterinarias, Hospital Veterinario Universitario Rof Codina, Facultad de Veterinaria, Universidad de Santiago de Compostel, Lugo, Spain., Vieytes MR; Departamento de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain., Botana LM; Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2021 Jul 07; Vol. 12, pp. 694639. Date of Electronic Publication: 2021 Jul 07 (Print Publication: 2021).
DOI:	10.3389/fphar.2021.694639
Abstrakt:	Crambescins are guanidine alkaloids from the sponge Crambe crambe . Crambescin C1 (CC) induces metallothionein genes and nitric oxide (NO) is one of the triggers. We studied and compared the in vitro , in vivo, and in silico effects of some crambescine A and C analogs. HepG2 gene expression was analyzed using microarrays. Vasodilation was studied in rat aortic rings. In vivo hypotensive effect was directly measured in anesthetized rats. The targets of crambescines were studied in silico . CC and homo-crambescine C1 (HCC), but not crambescine A1 (CA), induced metallothioneins transcripts. CC increased NO production in HepG2 cells. In isolated rat aortic rings, CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone. In silico analysis also points to eNOS and iNOS as targets of Crambescin C1 and source of NO increment. CC effect is mediated through crambescin binding to the active site of eNOS and iNOS. CC docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than CA. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production. Our results suggest that CC serve as a basis to develop new useful drugs when bioavailability of NO is perturbed. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Rubiolo, Lence, González-Bello, Roel, Gil-Longo, Campos-Toimil, Ternon, Thomas, González-Cantalapiedra, López-Alonso, Vieytes and Botana.)
Databáze:	MEDLINE
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