Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression
Abstract Background The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate atherosclerosis progression. Plaque instability, the fundamental pathological factor...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Cellular & Molecular Biology Letters |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s11658-025-00720-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850265468167782400 |
|---|---|
| author | Ping Li Yixiao Xiang Jinzhi Wei Xingyan Xu Jiale Wang Haowei Yu Xiaosa Li Huiping Lin Xiaodong Fu |
| author_facet | Ping Li Yixiao Xiang Jinzhi Wei Xingyan Xu Jiale Wang Haowei Yu Xiaosa Li Huiping Lin Xiaodong Fu |
| author_sort | Ping Li |
| collection | DOAJ |
| description | Abstract Background The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate atherosclerosis progression. Plaque instability, the fundamental pathological factor in acute coronary syndrome, primarily results from vascular embolism due to plaque rupture. Recent evidence highlights that endothelial-to-mesenchymal transition (EndMT) exacerbates plaque instability, although the link between FSH and EndMT has not been fully established. This investigation sought to explore the possible influence of FSH in modulating EndMT. Methods In this study, apolipoprotein E-deficient (ApoE −/−) mice served as an atherosclerosis model, while human umbilical vascular endothelial cells (HUVECs) were used as cellular models. Protein levels were assessed through immunochemical techniques, gene expression was quantified via RT-qPCR, and nucleic acid–protein interactions were evaluated using immunoprecipitation. The m6A modification status was determined by MeRIP, and cellular behaviors were analyzed through standard biochemical assays. Results Our results indicate that FSH induces EndMT both in vitro and in vivo. Additional investigation suggested that FSH upregulates the transcription factor Forkhead box protein M1 (FOXM1) at both protein and mRNA levels by enhancing the expression of AlkB homolog 5, RNA demethylase (ALKBH5). FSH reduces m6A modifications on FOXM1 through ALKBH5, leading to increased nascent transcript levels and mRNA stability of FOXM1. Dual-luciferase reporter assays highlighted cAMP-response element binding protein (CREB)’s essential function in facilitating the FSH-induced upregulation of ALKBH5. Conclusions These findings suggest that FSH promotes ALKBH5 expression, facilitates N 6-methyladenosine (m6A) demethylation on FOXM1, and consequently, induces EndMT. This study elucidates the impact of FSH on plaque instability and provides insights into potential strategies to prevent acute coronary syndrome in postmenopausal women. Graphical Abstract |
| format | Article |
| id | doaj-art-2cdc2728c9824d8eac64eadd6b6600a4 |
| institution | OA Journals |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-2cdc2728c9824d8eac64eadd6b6600a42025-08-20T01:54:25ZengBMCCellular & Molecular Biology Letters1689-13922025-04-0130112210.1186/s11658-025-00720-yFollicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expressionPing Li0Yixiao Xiang1Jinzhi Wei2Xingyan Xu3Jiale Wang4Haowei Yu5Xiaosa Li6Huiping Lin7Xiaodong Fu8The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical UniversityKey Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical UniversityKey Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical UniversityThe Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical UniversityAbstract Background The incidence of atherosclerosis markedly rises following menopause. Our previous findings demonstrated that elevated follicle-stimulating hormone (FSH) levels in postmenopausal women accelerate atherosclerosis progression. Plaque instability, the fundamental pathological factor in acute coronary syndrome, primarily results from vascular embolism due to plaque rupture. Recent evidence highlights that endothelial-to-mesenchymal transition (EndMT) exacerbates plaque instability, although the link between FSH and EndMT has not been fully established. This investigation sought to explore the possible influence of FSH in modulating EndMT. Methods In this study, apolipoprotein E-deficient (ApoE −/−) mice served as an atherosclerosis model, while human umbilical vascular endothelial cells (HUVECs) were used as cellular models. Protein levels were assessed through immunochemical techniques, gene expression was quantified via RT-qPCR, and nucleic acid–protein interactions were evaluated using immunoprecipitation. The m6A modification status was determined by MeRIP, and cellular behaviors were analyzed through standard biochemical assays. Results Our results indicate that FSH induces EndMT both in vitro and in vivo. Additional investigation suggested that FSH upregulates the transcription factor Forkhead box protein M1 (FOXM1) at both protein and mRNA levels by enhancing the expression of AlkB homolog 5, RNA demethylase (ALKBH5). FSH reduces m6A modifications on FOXM1 through ALKBH5, leading to increased nascent transcript levels and mRNA stability of FOXM1. Dual-luciferase reporter assays highlighted cAMP-response element binding protein (CREB)’s essential function in facilitating the FSH-induced upregulation of ALKBH5. Conclusions These findings suggest that FSH promotes ALKBH5 expression, facilitates N 6-methyladenosine (m6A) demethylation on FOXM1, and consequently, induces EndMT. This study elucidates the impact of FSH on plaque instability and provides insights into potential strategies to prevent acute coronary syndrome in postmenopausal women. Graphical Abstracthttps://doi.org/10.1186/s11658-025-00720-yFollicle-stimulating hormone (FSH)Endothelial to mesenchymal transition (EndMT)FOXM1ALKBH5 |
| spellingShingle | Ping Li Yixiao Xiang Jinzhi Wei Xingyan Xu Jiale Wang Haowei Yu Xiaosa Li Huiping Lin Xiaodong Fu Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression Cellular & Molecular Biology Letters Follicle-stimulating hormone (FSH) Endothelial to mesenchymal transition (EndMT) FOXM1 ALKBH5 |
| title | Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression |
| title_full | Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression |
| title_fullStr | Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression |
| title_full_unstemmed | Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression |
| title_short | Follicle-stimulating hormone promotes EndMT in endothelial cells by upregulating ALKBH5 expression |
| title_sort | follicle stimulating hormone promotes endmt in endothelial cells by upregulating alkbh5 expression |
| topic | Follicle-stimulating hormone (FSH) Endothelial to mesenchymal transition (EndMT) FOXM1 ALKBH5 |
| url | https://doi.org/10.1186/s11658-025-00720-y |
| work_keys_str_mv | AT pingli folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT yixiaoxiang folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT jinzhiwei folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT xingyanxu folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT jialewang folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT haoweiyu folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT xiaosali folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT huipinglin folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression AT xiaodongfu folliclestimulatinghormonepromotesendmtinendothelialcellsbyupregulatingalkbh5expression |