Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axis
Background: Myocardial ischemia-reperfusion (I/R) induced cardiomyocyte death is a major cause of cardiac dysfunction and fibrosis. Ferroptosis of cardiomyocytes has been demonstrated to contribute to I/R induced injury. Qiangyang decoction (QYD) is commonly used in clinical treatment of hypertensio...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Pharmacological Research - Modern Chinese Medicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667142524002021 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850053982259511296 |
|---|---|
| author | Jing Wang Wan Cai Jingxuan Chen Wenjin Wang Wentao Fu Wen Ge Hao Chi |
| author_facet | Jing Wang Wan Cai Jingxuan Chen Wenjin Wang Wentao Fu Wen Ge Hao Chi |
| author_sort | Jing Wang |
| collection | DOAJ |
| description | Background: Myocardial ischemia-reperfusion (I/R) induced cardiomyocyte death is a major cause of cardiac dysfunction and fibrosis. Ferroptosis of cardiomyocytes has been demonstrated to contribute to I/R induced injury. Qiangyang decoction (QYD) is commonly used in clinical treatment of hypertension and cardiac fibrosis. However, the intervention effect of QYD on I/R injury, especially its therapeutic efficacy on ferroptosis in cardiomyocytes, remains unclear. This study aimed to investigate the effect of QYD against I/R induced cardiomyocyte ferroptosis and to reveal the underlying mechanism. Methods: In this study, UPLC-MS/MS was conducted to identify the component of QYD. An in vivo I/R mouse model and an in vitro cardiomyocytes OGD model were utilized to evaluate the cardiac protective effect of QYD. Transcriptome analysis and western blotting assays were used to explore the mechanism. Results: A high dose of QYD exerts a cardioprotective effect through inhibiting I/R-induced cardiomyocyte ferroptosis. A high dose of QYD ameliorated I/R and OGD injury; these beneficial effects were not further enhanced by the ferroptosis inhibitor Fer-1. Anti-ferroptosis factors FPN1, Homx1, and GPX4 were transcriptionally upregulated by QYD both in mouse heart and adult mouse cardiomyocytes (AMCMs). Consistently, the kelch like ECH associated protein 1 (KEAP1) level and nuclear factor erythroid 2-related factor 2 (Nrf2) degradation were remarkably suppressed. RNA-sequencing results revealed that unc-51 like autophagy activating kinase 1 (ULK1), a serine kinase mediating the autophagy-dependent degradation of KEAP1, was significantly up-regulated in QYD-treated mouse hearts. The ULK1 inhibitor SBI-0206965 abolished the inhibition of QYD on KEAP1 and notably weakened the cardiac protective effect. Conclusions: These findings suggest that QYD exerted cardiac protection by activating ULK1 and subsequently inhibited KEAP1, thereby enhancing Nrf2 level and initiating the transcription of ferroptosis-resistance genes. These findings highlight that QYD may serve as a cardioprotective strategy for I/R. |
| format | Article |
| id | doaj-art-2bd94f71876c4fad839a3eff4249f140 |
| institution | DOAJ |
| issn | 2667-1425 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research - Modern Chinese Medicine |
| spelling | doaj-art-2bd94f71876c4fad839a3eff4249f1402025-08-20T02:52:24ZengElsevierPharmacological Research - Modern Chinese Medicine2667-14252025-03-011410056010.1016/j.prmcm.2024.100560Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axisJing Wang0Wan Cai1Jingxuan Chen2Wenjin Wang3Wentao Fu4Wen Ge5Hao Chi6Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Shanghai 201203, ChinaShuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Shanghai 201203, ChinaDepartment of Cardiothoracic Surgery, The 900 Hospital of the Joint Service Support Force of the People's Liberation Army of China, Fuzhou 350025, ChinaThe First Affiliated Hospital of Tsinghua University, Beijing 200016, ChinaShuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Shanghai 201203, ChinaShuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Shanghai 201203, ChinaShuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhang Heng Road, Shanghai 201203, China; Corresponding author.Background: Myocardial ischemia-reperfusion (I/R) induced cardiomyocyte death is a major cause of cardiac dysfunction and fibrosis. Ferroptosis of cardiomyocytes has been demonstrated to contribute to I/R induced injury. Qiangyang decoction (QYD) is commonly used in clinical treatment of hypertension and cardiac fibrosis. However, the intervention effect of QYD on I/R injury, especially its therapeutic efficacy on ferroptosis in cardiomyocytes, remains unclear. This study aimed to investigate the effect of QYD against I/R induced cardiomyocyte ferroptosis and to reveal the underlying mechanism. Methods: In this study, UPLC-MS/MS was conducted to identify the component of QYD. An in vivo I/R mouse model and an in vitro cardiomyocytes OGD model were utilized to evaluate the cardiac protective effect of QYD. Transcriptome analysis and western blotting assays were used to explore the mechanism. Results: A high dose of QYD exerts a cardioprotective effect through inhibiting I/R-induced cardiomyocyte ferroptosis. A high dose of QYD ameliorated I/R and OGD injury; these beneficial effects were not further enhanced by the ferroptosis inhibitor Fer-1. Anti-ferroptosis factors FPN1, Homx1, and GPX4 were transcriptionally upregulated by QYD both in mouse heart and adult mouse cardiomyocytes (AMCMs). Consistently, the kelch like ECH associated protein 1 (KEAP1) level and nuclear factor erythroid 2-related factor 2 (Nrf2) degradation were remarkably suppressed. RNA-sequencing results revealed that unc-51 like autophagy activating kinase 1 (ULK1), a serine kinase mediating the autophagy-dependent degradation of KEAP1, was significantly up-regulated in QYD-treated mouse hearts. The ULK1 inhibitor SBI-0206965 abolished the inhibition of QYD on KEAP1 and notably weakened the cardiac protective effect. Conclusions: These findings suggest that QYD exerted cardiac protection by activating ULK1 and subsequently inhibited KEAP1, thereby enhancing Nrf2 level and initiating the transcription of ferroptosis-resistance genes. These findings highlight that QYD may serve as a cardioprotective strategy for I/R.http://www.sciencedirect.com/science/article/pii/S2667142524002021FerroptosisQiangyang decoctionKEAP1Nrf2ULK1 |
| spellingShingle | Jing Wang Wan Cai Jingxuan Chen Wenjin Wang Wentao Fu Wen Ge Hao Chi Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axis Pharmacological Research - Modern Chinese Medicine Ferroptosis Qiangyang decoction KEAP1 Nrf2 ULK1 |
| title | Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axis |
| title_full | Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axis |
| title_fullStr | Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axis |
| title_full_unstemmed | Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axis |
| title_short | Qiangyang decoction attenuates ischemia/reperfusion-induced cardiomyocyte ferroptosis via ULK1/KEAP1/Nrf2 axis |
| title_sort | qiangyang decoction attenuates ischemia reperfusion induced cardiomyocyte ferroptosis via ulk1 keap1 nrf2 axis |
| topic | Ferroptosis Qiangyang decoction KEAP1 Nrf2 ULK1 |
| url | http://www.sciencedirect.com/science/article/pii/S2667142524002021 |
| work_keys_str_mv | AT jingwang qiangyangdecoctionattenuatesischemiareperfusioninducedcardiomyocyteferroptosisviaulk1keap1nrf2axis AT wancai qiangyangdecoctionattenuatesischemiareperfusioninducedcardiomyocyteferroptosisviaulk1keap1nrf2axis AT jingxuanchen qiangyangdecoctionattenuatesischemiareperfusioninducedcardiomyocyteferroptosisviaulk1keap1nrf2axis AT wenjinwang qiangyangdecoctionattenuatesischemiareperfusioninducedcardiomyocyteferroptosisviaulk1keap1nrf2axis AT wentaofu qiangyangdecoctionattenuatesischemiareperfusioninducedcardiomyocyteferroptosisviaulk1keap1nrf2axis AT wenge qiangyangdecoctionattenuatesischemiareperfusioninducedcardiomyocyteferroptosisviaulk1keap1nrf2axis AT haochi qiangyangdecoctionattenuatesischemiareperfusioninducedcardiomyocyteferroptosisviaulk1keap1nrf2axis |