RT Journal Article
T1 Crambescin C1 acts as a possible substrate of iNOS and eNOS increasing nitric oxide production and inducing in vivo hypotensive effect
A1 Rubiolo Gaytán, Juan Andrés
A1 Lence Quintana, Emilio José
A1 González Bello, Concepción
A1 Roel Fernández, María
A1 Gil Longo, José
A1 Campos Toimil, Manuel
A1 Ternon, Eva
A1 Thomas, Olivier P.
A1 González Cantalapiedra, Antonio
A1 López Alonso, Henar
A1 Rodríguez Vieytes, Mercedes
A1 Botana López, Luis Miguel
K1 Crambescin
K1 Nitric oxide synthase
K1 Docking
K1 Molecular dynamics simulations
K1 Hypotension
K1 Metallothionein
K1 HepG2 cells
AB 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
PB Frontiers
SN 1663-9812
YR 2021
FD 2021-07-07
LK https://hdl.handle.net/10347/45176
UL https://hdl.handle.net/10347/45176
LA eng
NO Rubiolo JA, Lence E, González-Bello C, Roel M, Gil-Longo J, Campos-Toimil M, Ternon E, Thomas OP, González-Cantalapiedra A, López-Alonso H, Vieytes MR and Botana LM (2021) Crambescin C1 Acts as A Possible Substrate of iNOS and eNOS Increasing Nitric Oxide Production and Inducing In Vivo Hypotensive Effect. Front. Pharmacol. 12:694639. doi: 10.3389/fphar.2021.694639
NO The research leading to these results has received funding from the following FEDER cofunded-grants. From Conselleria de Cultura, Educacion e Ordenación Universitaria, Xunta de Galicia, GRC (ED431C 2021/01). GPC (ED431B 2018/04) and Centro singular de investigación de Galicia accreditation 2019–2022 (ED431G 2019/03). From Ministerio de Ciencia e Innovación IISCIII/PI19/001248 and PID2019-105512RB-I00. From European Union Interreg AlertoxNet EAPA-317–2016, Interreg Agritox EAPA-998–2018, and H2020 778069-EMERTOX
DS Minerva
RD 23 may 2026