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Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells

Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been clinically proven to protect endothelial function. Previously, we demonstrated that endothelial NO synthase (eNOS) was activated by high-density lipoprotein (HDL) via its scavenger receptor of the B class/human homologue of SR-BI, CD36 and...

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Autores principales: Lyu, Jingya, Imachi, Hitomi, Fukunaga, Kensaku, Sato, Seisuke, Kobayashi, Toshihiro, Saheki, Takanobu, Japar, Salimah, Iwama, Hisakazu, Matsumura, Yuta, Ozaki, Miyo, Yoshimura, Takafumi, Murao, Koji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9689235/
https://www.ncbi.nlm.nih.gov/pubmed/36354682
http://dx.doi.org/10.3390/cimb44110370
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author Lyu, Jingya
Imachi, Hitomi
Fukunaga, Kensaku
Sato, Seisuke
Kobayashi, Toshihiro
Saheki, Takanobu
Japar, Salimah
Iwama, Hisakazu
Matsumura, Yuta
Ozaki, Miyo
Yoshimura, Takafumi
Murao, Koji
author_facet Lyu, Jingya
Imachi, Hitomi
Fukunaga, Kensaku
Sato, Seisuke
Kobayashi, Toshihiro
Saheki, Takanobu
Japar, Salimah
Iwama, Hisakazu
Matsumura, Yuta
Ozaki, Miyo
Yoshimura, Takafumi
Murao, Koji
author_sort Lyu, Jingya
collection PubMed
description Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been clinically proven to protect endothelial function. Previously, we demonstrated that endothelial NO synthase (eNOS) was activated by high-density lipoprotein (HDL) via its scavenger receptor of the B class/human homologue of SR-BI, CD36 and LIMPII analogous-1(hSR-BI/CLA-1). Here, we investigated the effect of GLP-1RA and exendin-4 on the expression of hSR-BI/CLA-1 in HUVECs. Our results confirmed that GLP-1R was expressed in HUVECs by PCR and exendin-4 significantly enhanced HDL-induced eNOS activation. Next, exendin-4 increased the expression of hSR-BI/CLA-1 and a blockade of GLP-1R cancelled this effect. Further, the hSR-BI/CLA-1 transcriptional activity was enhanced by exendin-4, which was diminished by the inhibition of AMPK or dominant-negative AMPK-α-subunit. Moreover, AMPK was phosphorylated by the activation of GLP-1R. Next, ChIP assay demonstrated that exendin-4 increased the FoxO1-binding in the hSR-BI/CLA-1 promoter by upregulation of FoxO1. Mutation of FoxO1-binding or silencing of FoxO1 cancelled the effect of exendin-4 on hSR-BI/CLA-1 expression. Exendin-4 reduced FoxO1 phosphorylation and induced its nuclear accumulation, while this effect was altered by the blocking of GLP-1R or inhibition of AMPK pathway. In summary, our results proved that exendin-4 increased hSR-BI/CLA-1 expression via the AMPK/FoxO1 pathway to activate eNOS, providing a basic mechanism underlining the protective effect of GLP-1RA on endothelial function.
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spelling pubmed-96892352022-11-25 Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells Lyu, Jingya Imachi, Hitomi Fukunaga, Kensaku Sato, Seisuke Kobayashi, Toshihiro Saheki, Takanobu Japar, Salimah Iwama, Hisakazu Matsumura, Yuta Ozaki, Miyo Yoshimura, Takafumi Murao, Koji Curr Issues Mol Biol Article Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been clinically proven to protect endothelial function. Previously, we demonstrated that endothelial NO synthase (eNOS) was activated by high-density lipoprotein (HDL) via its scavenger receptor of the B class/human homologue of SR-BI, CD36 and LIMPII analogous-1(hSR-BI/CLA-1). Here, we investigated the effect of GLP-1RA and exendin-4 on the expression of hSR-BI/CLA-1 in HUVECs. Our results confirmed that GLP-1R was expressed in HUVECs by PCR and exendin-4 significantly enhanced HDL-induced eNOS activation. Next, exendin-4 increased the expression of hSR-BI/CLA-1 and a blockade of GLP-1R cancelled this effect. Further, the hSR-BI/CLA-1 transcriptional activity was enhanced by exendin-4, which was diminished by the inhibition of AMPK or dominant-negative AMPK-α-subunit. Moreover, AMPK was phosphorylated by the activation of GLP-1R. Next, ChIP assay demonstrated that exendin-4 increased the FoxO1-binding in the hSR-BI/CLA-1 promoter by upregulation of FoxO1. Mutation of FoxO1-binding or silencing of FoxO1 cancelled the effect of exendin-4 on hSR-BI/CLA-1 expression. Exendin-4 reduced FoxO1 phosphorylation and induced its nuclear accumulation, while this effect was altered by the blocking of GLP-1R or inhibition of AMPK pathway. In summary, our results proved that exendin-4 increased hSR-BI/CLA-1 expression via the AMPK/FoxO1 pathway to activate eNOS, providing a basic mechanism underlining the protective effect of GLP-1RA on endothelial function. MDPI 2022-11-03 /pmc/articles/PMC9689235/ /pubmed/36354682 http://dx.doi.org/10.3390/cimb44110370 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lyu, Jingya
Imachi, Hitomi
Fukunaga, Kensaku
Sato, Seisuke
Kobayashi, Toshihiro
Saheki, Takanobu
Japar, Salimah
Iwama, Hisakazu
Matsumura, Yuta
Ozaki, Miyo
Yoshimura, Takafumi
Murao, Koji
Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells
title Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells
title_full Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells
title_fullStr Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells
title_full_unstemmed Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells
title_short Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells
title_sort exendin-4 increases scavenger receptor class bi expression via activation of ampk/foxo1 in human vascular endothelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9689235/
https://www.ncbi.nlm.nih.gov/pubmed/36354682
http://dx.doi.org/10.3390/cimb44110370
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