Cargando…

Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas

BACKGROUND: Pravastatin, a known inducer of endothelial nitric-oxide synthase (eNOS) was demonstrated in human placenta, however the exact mechanism of it’s action is not fully understood. Since placental NO (nitric oxide) synthesis is of primary importance in the regulation of placental blood flow,...

Descripción completa

Detalles Bibliográficos
Autores principales: Pánczél, Zita, Kukor, Zoltán, Supák, Dorina, Kovács, Bence, Kecskeméti, András, Czizel, Rita, Djurecz, Magdolna, Alasztics, Bálint, Csomó, Krisztián Benedek, Hrabák, András, Valent, Sándor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868828/
https://www.ncbi.nlm.nih.gov/pubmed/31747921
http://dx.doi.org/10.1186/s12884-019-2507-0
_version_ 1783472353178550272
author Pánczél, Zita
Kukor, Zoltán
Supák, Dorina
Kovács, Bence
Kecskeméti, András
Czizel, Rita
Djurecz, Magdolna
Alasztics, Bálint
Csomó, Krisztián Benedek
Hrabák, András
Valent, Sándor
author_facet Pánczél, Zita
Kukor, Zoltán
Supák, Dorina
Kovács, Bence
Kecskeméti, András
Czizel, Rita
Djurecz, Magdolna
Alasztics, Bálint
Csomó, Krisztián Benedek
Hrabák, András
Valent, Sándor
author_sort Pánczél, Zita
collection PubMed
description BACKGROUND: Pravastatin, a known inducer of endothelial nitric-oxide synthase (eNOS) was demonstrated in human placenta, however the exact mechanism of it’s action is not fully understood. Since placental NO (nitric oxide) synthesis is of primary importance in the regulation of placental blood flow, we aimed to clarify the effects of pravastatin on healthy (n = 6) and preeclamptic (n = 6) placentas (Caucasian participants). METHODS: The eNOS activity of human placental microsomes was determined by the conversion rate of C14 L-arginine into C14 L-citrulline with or without pravastatin and Geldanamycin. Phosphorylation of eNOS (Ser1177) was investigated by Western blot. Microsomal arginine uptake was measured by a rapid filtration method. RESULTS: Pravastatin significantly increased total eNOS activity in healthy (28%, p<0.05) and preeclamptic placentas (32%, p<0.05) using 1 mM Ca(2+) promoting the dissociation of a eNOS from it’s inhibitor caveolin. Pravastatin and Geldanamycin (Hsp90 inhibitor) cotreatment increased microsomal eNOS activity. Pravastatin treatment had no significant effects on Ser1177 phosphorylation of eNOS in either healthy or preeclamptic placentas. Pravastatin induced arginine uptake of placental microsomes in both healthy (38%, p < 0.05) and preeclamptic pregnancies (34%, p < 0.05). CONCLUSIONS: This study provides a novel mechanism of pravastatin action on placental NO metabolism. Pravastatin induces the placental microsomal arginine uptake leading to the rapid activation of eNOS independently of Ser1177 phosphorylation. These new findings may contribute to better understanding of preeclampsia and may also have a clinical relevance.
format Online
Article
Text
id pubmed-6868828
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-68688282019-12-12 Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas Pánczél, Zita Kukor, Zoltán Supák, Dorina Kovács, Bence Kecskeméti, András Czizel, Rita Djurecz, Magdolna Alasztics, Bálint Csomó, Krisztián Benedek Hrabák, András Valent, Sándor BMC Pregnancy Childbirth Research Article BACKGROUND: Pravastatin, a known inducer of endothelial nitric-oxide synthase (eNOS) was demonstrated in human placenta, however the exact mechanism of it’s action is not fully understood. Since placental NO (nitric oxide) synthesis is of primary importance in the regulation of placental blood flow, we aimed to clarify the effects of pravastatin on healthy (n = 6) and preeclamptic (n = 6) placentas (Caucasian participants). METHODS: The eNOS activity of human placental microsomes was determined by the conversion rate of C14 L-arginine into C14 L-citrulline with or without pravastatin and Geldanamycin. Phosphorylation of eNOS (Ser1177) was investigated by Western blot. Microsomal arginine uptake was measured by a rapid filtration method. RESULTS: Pravastatin significantly increased total eNOS activity in healthy (28%, p<0.05) and preeclamptic placentas (32%, p<0.05) using 1 mM Ca(2+) promoting the dissociation of a eNOS from it’s inhibitor caveolin. Pravastatin and Geldanamycin (Hsp90 inhibitor) cotreatment increased microsomal eNOS activity. Pravastatin treatment had no significant effects on Ser1177 phosphorylation of eNOS in either healthy or preeclamptic placentas. Pravastatin induced arginine uptake of placental microsomes in both healthy (38%, p < 0.05) and preeclamptic pregnancies (34%, p < 0.05). CONCLUSIONS: This study provides a novel mechanism of pravastatin action on placental NO metabolism. Pravastatin induces the placental microsomal arginine uptake leading to the rapid activation of eNOS independently of Ser1177 phosphorylation. These new findings may contribute to better understanding of preeclampsia and may also have a clinical relevance. BioMed Central 2019-11-20 /pmc/articles/PMC6868828/ /pubmed/31747921 http://dx.doi.org/10.1186/s12884-019-2507-0 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Pánczél, Zita
Kukor, Zoltán
Supák, Dorina
Kovács, Bence
Kecskeméti, András
Czizel, Rita
Djurecz, Magdolna
Alasztics, Bálint
Csomó, Krisztián Benedek
Hrabák, András
Valent, Sándor
Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
title Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
title_full Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
title_fullStr Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
title_full_unstemmed Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
title_short Pravastatin induces NO synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
title_sort pravastatin induces no synthesis by enhancing microsomal arginine uptake in healthy and preeclamptic placentas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868828/
https://www.ncbi.nlm.nih.gov/pubmed/31747921
http://dx.doi.org/10.1186/s12884-019-2507-0
work_keys_str_mv AT panczelzita pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT kukorzoltan pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT supakdorina pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT kovacsbence pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT kecskemetiandras pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT czizelrita pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT djureczmagdolna pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT alaszticsbalint pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT csomokrisztianbenedek pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT hrabakandras pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas
AT valentsandor pravastatininducesnosynthesisbyenhancingmicrosomalarginineuptakeinhealthyandpreeclampticplacentas