Abstract | AIMS: METHODS: Mouse and cultured cardiomyocytes (neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes) I/R models were used to investigate the effects of SAHA on mitochondria. ATG7 knockout mice, ATG7 knockdown by siRNA and PGC-1α knockdown by adenovirus in cardiomyocytes were used to test the dependency of autophagy and PGC-1α-mediated mitochondrial biogenesis respectively. RESULTS: Intact and total mitochondrial DNA ( mtDNA) content and mitochondrial mass were significantly increased in cardiomyocytes by SAHA pretreatment before simulated I/R. In vivo, I/R induced >50% loss of mtDNA content in the border zones of mouse hearts, but SAHA pretreatment and reperfusion treatment alone reverted mtDNA content and mitochondrial mass to control levels. Moreover, pretreatment of cardiomyocytes with SAHA resulted in a 4-fold decrease in I/R-induced loss of mitochondrial membrane potential and a 25%-40% reduction in cytosolic ROS levels. However, loss-of-function of ATG7 in cardiomyocytes or mouse myocardium abolished the protective effects of SAHA on ROS levels, mitochondrial membrane potential, mtDNA levels, and mitochondrial mass. Lastly, PGC-1α gene expression was induced by SAHA in NRVMs and mouse heart subjected to I/R, and loss of PGC-1α abrogated SAHA's mitochondrial protective effects in cardiomyocytes. CONCLUSIONS: SAHA prevents I/R induced- mitochondrial dysfunction and loss, and reduces myocardial ROS production when given before or after the ischemia. The protective effects of SAHA on mitochondria are dependent on autophagy and PGC-1α-mediated mitochondrial biogenesis.
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Authors | Jing Yang, Jin He, Mahmoud Ismail, Sonja Tweeten, Fanfang Zeng, Ling Gao, Scott Ballinger, Martin Young, Sumanth D Prabhu, Glenn C Rowe, Jianyi Zhang, Lufang Zhou, Min Xie |
Journal | Journal of molecular and cellular cardiology
(J Mol Cell Cardiol)
Vol. 130
Pg. 36-48
(05 2019)
ISSN: 1095-8584 [Electronic] England |
PMID | 30880250
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2019 Elsevier Ltd. All rights reserved. |
Chemical References |
- Cardiotonic Agents
- Histone Deacetylase Inhibitors
- Reactive Oxygen Species
- Vorinostat
|
Topics |
- Animals
- Autophagic Cell Death
- Cardiotonic Agents
(pharmacology)
- Disease Models, Animal
- Histone Deacetylase Inhibitors
(pharmacology)
- Humans
- Mice
- Mice, Knockout
- Mitochondria, Heart
(genetics, metabolism, pathology)
- Myocardial Reperfusion Injury
(drug therapy, genetics, metabolism, pathology)
- Myocytes, Cardiac
(metabolism)
- Rats
- Rats, Sprague-Dawley
- Reactive Oxygen Species
(metabolism)
- Vorinostat
(pharmacology)
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