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Hypertrophic preconditioning attenuates post-myocardial infarction injury through deacetylation of isocitrate dehydrogenase 2
- Source :
- Acta Pharmacol Sin
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- Ischemic preconditioning induced by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischemic insult. In this study we investigated whether a short-term nonischemic stimulation of hypertrophy renders the heart resistant to subsequent ischemic injury. Male mice were subjected to transient transverse aortic constriction (TAC) for 3 days followed aortic debanding on D4 (T3D4), as well as ligation of the left coronary artery to induce myocardial infarction (MI). The TAC preconditioning mice showed markedly improved contractile function and significantly reduced myocardial fibrotic area and apoptosis following MI. We revealed that TAC preconditioning significantly reduced MI-induced oxidative stress, evidenced by increased NADPH/NADP ratio and GSH/GSSG ratio, as well as decreased mitochondrial ROS production. Furthermore, TAC preconditioning significantly increased the expression and activity of SIRT3 protein following MI. Cardiac-specific overexpression of SIRT3 gene through in vivo AAV-SIRT3 transfection partially mimicked the protective effects of TAC preconditioning, whereas genetic ablation of SIRT3 in mice blocked the protective effects of TAC preconditioning. Moreover, expression of an IDH2 mutant mimicking deacetylation (IDH2 K413R) in cardiomyocytes promoted myocardial IDH2 activation, quenched mitochondrial reactive oxygen species (ROS), and alleviated post-MI injury, whereas expression of an acetylation mimic (IDH2 K413Q) in cardiomyocytes inactivated IDH2, exacerbated mitochondrial ROS overload, and aggravated post-MI injury. In conclusion, this study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Therapeutic strategies targeting IDH2 are promising treatment approaches for cardiac ischemic injury.
- Subjects :
- Male
0301 basic medicine
Mitochondrial ROS
SIRT3
Myocardial Infarction
Apoptosis
Pharmacology
medicine.disease_cause
Article
Muscle hypertrophy
Gene Knockout Techniques
03 medical and health sciences
0302 clinical medicine
Sirtuin 3
Animals
Medicine
Pharmacology (medical)
Myocardial infarction
Mice, Knockout
chemistry.chemical_classification
Reactive oxygen species
business.industry
Acetylation
General Medicine
medicine.disease
Isocitrate Dehydrogenase
Mitochondria
Mice, Inbred C57BL
Oxidative Stress
030104 developmental biology
chemistry
Coronary occlusion
030220 oncology & carcinogenesis
Ischemic Preconditioning, Myocardial
Mutation
Ischemic preconditioning
Reactive Oxygen Species
business
Oxidative stress
Subjects
Details
- ISSN :
- 17457254 and 16714083
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Acta Pharmacologica Sinica
- Accession number :
- edsair.doi.dedup.....1bc5de427df4e14048e1e3af7115961d