Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway
Hypertension-induced cardiac apoptosis is a major contributor to early-stage heart-failure. Our previous studies have found that p53-mediated mitochondrial fission is involved in aldosterone-induced podocyte apoptosis. However, it is not clear that whether p53-induced mitochondrial fission is critic...
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| Format: | Article |
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2018.00176/full |
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| author | Jia Qi Jia Qi Feng Wang Ping Yang Xuelian Wang Renjie Xu Jihui Chen Yanggang Yuan Zhaoyang Lu Zhaoyang Lu Junli Duan |
| author_facet | Jia Qi Jia Qi Feng Wang Ping Yang Xuelian Wang Renjie Xu Jihui Chen Yanggang Yuan Zhaoyang Lu Zhaoyang Lu Junli Duan |
| author_sort | Jia Qi |
| collection | DOAJ |
| description | Hypertension-induced cardiac apoptosis is a major contributor to early-stage heart-failure. Our previous studies have found that p53-mediated mitochondrial fission is involved in aldosterone-induced podocyte apoptosis. However, it is not clear that whether p53-induced mitochondrial fission is critical for hypertensive Angiotensin II (AngII)-induced cardiomyocyte apoptosis. In this study, we found that inhibition of the mitochondrial fission protein Drp1 (dynamin-related protein 1) by Mdivi-1 prevented cardiomyocyte apoptosis and cardiac remodeling in SHRs. In vitro we found that treatment of cultured neonatal rat cardiomyocytes with AngII induced Drp1 expression, mitochondrial fission, and apoptosis. Knockdown of Drp1 inhibited AngII-induced mitochondrial fission and cardiomyocyte apoptosis. Furthermore, AngII induced p53 acetylation. Knockdown of p53 inhibited AngII-induced Drp1 expression, mitochondrial fission, and cardiomyocyte apoptosis. Besides, we found that Sirt1 was able to reverse AngII-induced p53 acetylation and its binding to the Drp1 promoter, which subsequently inhibited mitochondrial fission and eventually attenuated cardiomyocyte apoptosis. Collectively, these results suggest that AngII degrades Sirt1 to increase p53 acetylation, which induces Drp1 expression and eventually results in cardiomyocyte apoptosis. Sirt1/p53/Drp1dependent mitochondrial fission may be a valuable therapeutic target for hypertension induced heart failure. |
| first_indexed | 2024-04-13T00:58:58Z |
| format | Article |
| id | doaj.art-a206c30472114eaea81ea35ccebc7c2c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T00:58:58Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-a206c30472114eaea81ea35ccebc7c2c2022-12-22T03:09:32ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-03-01910.3389/fphar.2018.00176327978Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling PathwayJia Qi0Jia Qi1Feng Wang2Ping Yang3Xuelian Wang4Renjie Xu5Jihui Chen6Yanggang Yuan7Zhaoyang Lu8Zhaoyang Lu9Junli Duan10Department of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Gerontology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Neurology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Gerontology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Nephrology, First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Gerontology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaDepartment of Gerontology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, ChinaHypertension-induced cardiac apoptosis is a major contributor to early-stage heart-failure. Our previous studies have found that p53-mediated mitochondrial fission is involved in aldosterone-induced podocyte apoptosis. However, it is not clear that whether p53-induced mitochondrial fission is critical for hypertensive Angiotensin II (AngII)-induced cardiomyocyte apoptosis. In this study, we found that inhibition of the mitochondrial fission protein Drp1 (dynamin-related protein 1) by Mdivi-1 prevented cardiomyocyte apoptosis and cardiac remodeling in SHRs. In vitro we found that treatment of cultured neonatal rat cardiomyocytes with AngII induced Drp1 expression, mitochondrial fission, and apoptosis. Knockdown of Drp1 inhibited AngII-induced mitochondrial fission and cardiomyocyte apoptosis. Furthermore, AngII induced p53 acetylation. Knockdown of p53 inhibited AngII-induced Drp1 expression, mitochondrial fission, and cardiomyocyte apoptosis. Besides, we found that Sirt1 was able to reverse AngII-induced p53 acetylation and its binding to the Drp1 promoter, which subsequently inhibited mitochondrial fission and eventually attenuated cardiomyocyte apoptosis. Collectively, these results suggest that AngII degrades Sirt1 to increase p53 acetylation, which induces Drp1 expression and eventually results in cardiomyocyte apoptosis. Sirt1/p53/Drp1dependent mitochondrial fission may be a valuable therapeutic target for hypertension induced heart failure.http://journal.frontiersin.org/article/10.3389/fphar.2018.00176/fullmitochondrial fissioncardiomyocyte apoptosisAngiotensin IIhypertensionDrp1 |
| spellingShingle | Jia Qi Jia Qi Feng Wang Ping Yang Xuelian Wang Renjie Xu Jihui Chen Yanggang Yuan Zhaoyang Lu Zhaoyang Lu Junli Duan Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway Frontiers in Pharmacology mitochondrial fission cardiomyocyte apoptosis Angiotensin II hypertension Drp1 |
| title | Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway |
| title_full | Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway |
| title_fullStr | Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway |
| title_full_unstemmed | Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway |
| title_short | Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway |
| title_sort | mitochondrial fission is required for angiotensin ii induced cardiomyocyte apoptosis mediated by a sirt1 p53 signaling pathway |
| topic | mitochondrial fission cardiomyocyte apoptosis Angiotensin II hypertension Drp1 |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2018.00176/full |
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