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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | Current Issues in Molecular Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1467-3045/44/11/370 |
| _version_ | 1827646952372699136 |
|---|---|
| author | Jingya Lyu Hitomi Imachi Kensaku Fukunaga Seisuke Sato Toshihiro Kobayashi Takanobu Saheki Salimah Japar Hisakazu Iwama Yuta Matsumura Miyo Ozaki Takafumi Yoshimura Koji Murao |
| author_facet | Jingya Lyu Hitomi Imachi Kensaku Fukunaga Seisuke Sato Toshihiro Kobayashi Takanobu Saheki Salimah Japar Hisakazu Iwama Yuta Matsumura Miyo Ozaki Takafumi Yoshimura Koji Murao |
| author_sort | Jingya Lyu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T19:10:36Z |
| format | Article |
| id | doaj.art-a630a56a424b4be4bcbefd0af99c440b |
| institution | Directory Open Access Journal |
| issn | 1467-3037 1467-3045 |
| language | English |
| last_indexed | 2024-03-09T19:10:36Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj.art-a630a56a424b4be4bcbefd0af99c440b2023-11-24T04:13:15ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452022-11-0144115474548410.3390/cimb44110370Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial CellsJingya Lyu0Hitomi Imachi1Kensaku Fukunaga2Seisuke Sato3Toshihiro Kobayashi4Takanobu Saheki5Salimah Japar6Hisakazu Iwama7Yuta Matsumura8Miyo Ozaki9Takafumi Yoshimura10Koji Murao11Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, ChinaDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanLife Science Research Center, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Clinical Laboratory, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Clinical Laboratory, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, JapanGlucagon-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.https://www.mdpi.com/1467-3045/44/11/370human SR-BI/CLA-1activation of eNOSHDLGLP-1AMPK |
| spellingShingle | Jingya Lyu Hitomi Imachi Kensaku Fukunaga Seisuke Sato Toshihiro Kobayashi Takanobu Saheki Salimah Japar Hisakazu Iwama Yuta Matsumura Miyo Ozaki Takafumi Yoshimura Koji Murao Exendin-4 Increases Scavenger Receptor Class BI Expression via Activation of AMPK/FoxO1 in Human Vascular Endothelial Cells Current Issues in Molecular Biology human SR-BI/CLA-1 activation of eNOS HDL GLP-1 AMPK |
| 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 | human SR-BI/CLA-1 activation of eNOS HDL GLP-1 AMPK |
| url | https://www.mdpi.com/1467-3045/44/11/370 |
| work_keys_str_mv | AT jingyalyu exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT hitomiimachi exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT kensakufukunaga exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT seisukesato exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT toshihirokobayashi exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT takanobusaheki exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT salimahjapar exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT hisakazuiwama exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT yutamatsumura exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT miyoozaki exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT takafumiyoshimura exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells AT kojimurao exendin4increasesscavengerreceptorclassbiexpressionviaactivationofampkfoxo1inhumanvascularendothelialcells |