Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway
Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain u...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-02-01
|
| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S104366182400001X |
| _version_ | 1797322474314006528 |
|---|---|
| author | Zhangwei Chen Su Li Muyin Liu Ming Yin Jinxiang Chen Youran Li Qiyu Li You Zhou Yan Xia Ao Chen Danbo Lu Chenguang Li Yuqiong Chen Juying Qian Junbo Ge |
| author_facet | Zhangwei Chen Su Li Muyin Liu Ming Yin Jinxiang Chen Youran Li Qiyu Li You Zhou Yan Xia Ao Chen Danbo Lu Chenguang Li Yuqiong Chen Juying Qian Junbo Ge |
| author_sort | Zhangwei Chen |
| collection | DOAJ |
| description | Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction. |
| first_indexed | 2024-03-08T05:13:54Z |
| format | Article |
| id | doaj.art-31ad13f842204ca09357bdf88504836f |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-08T05:13:54Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-31ad13f842204ca09357bdf88504836f2024-02-07T04:42:11ZengElsevierPharmacological Research1096-11862024-02-01200107057Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathwayZhangwei Chen0Su Li1Muyin Liu2Ming Yin3Jinxiang Chen4Youran Li5Qiyu Li6You Zhou7Yan Xia8Ao Chen9Danbo Lu10Chenguang Li11Yuqiong Chen12Juying Qian13Junbo Ge14Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Corresponding authors.The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University; Corresponding authors.Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Corresponding authors.Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai 200032, ChinaMitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction.http://www.sciencedirect.com/science/article/pii/S104366182400001XMitochondria-associated ferroptosisCardiac microvascular dysfunctionDiabetic cardiomyopathyMitophagyAMPK signaling pathwayNicorandil |
| spellingShingle | Zhangwei Chen Su Li Muyin Liu Ming Yin Jinxiang Chen Youran Li Qiyu Li You Zhou Yan Xia Ao Chen Danbo Lu Chenguang Li Yuqiong Chen Juying Qian Junbo Ge Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway Pharmacological Research Mitochondria-associated ferroptosis Cardiac microvascular dysfunction Diabetic cardiomyopathy Mitophagy AMPK signaling pathway Nicorandil |
| title | Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway |
| title_full | Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway |
| title_fullStr | Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway |
| title_full_unstemmed | Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway |
| title_short | Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway |
| title_sort | nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy role of the mitochondria localized ampk parkin acsl4 signaling pathway |
| topic | Mitochondria-associated ferroptosis Cardiac microvascular dysfunction Diabetic cardiomyopathy Mitophagy AMPK signaling pathway Nicorandil |
| url | http://www.sciencedirect.com/science/article/pii/S104366182400001X |
| work_keys_str_mv | AT zhangweichen nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT suli nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT muyinliu nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT mingyin nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT jinxiangchen nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT youranli nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT qiyuli nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT youzhou nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT yanxia nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT aochen nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT danbolu nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT chenguangli nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT yuqiongchen nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT juyingqian nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway AT junboge nicorandilalleviatescardiacmicrovascularferroptosisindiabeticcardiomyopathyroleofthemitochondrialocalizedampkparkinacsl4signalingpathway |