SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms

Autor: Wei Jiang, Meijing Wang, Ye Zhu, Si si Wu, Heng yu Zhang, Ming ming Tong, Ru Li Li, Jia Xiang Chen, Yao Wu, Yan xin Li, Xiao Xiao Wang, Xu Lei Wang, Huali Chen, Jin han He, Lu Gan
Rok vydání: 2015
Předmět:
0301 basic medicine
Male
Physiology
Ischemia
Down-Regulation
Apoptosis
Myocardial Reperfusion Injury
030204 cardiovascular system & hematology
Pharmacology
AMP-Activated Protein Kinases
In Vitro Techniques
medicine.disease_cause
Antioxidants
Superoxide dismutase
Rats
Sprague-Dawley
03 medical and health sciences
Mice
0302 clinical medicine
Adenosine Triphosphate
Physiology (medical)
medicine
Animals
Sirtuins
Myocytes
Cardiac
Ventricular remodeling
Cells
Cultured
chemistry.chemical_classification
Cardioprotection
Reactive oxygen species
biology
Ventricular Remodeling
Superoxide Dismutase
Forkhead Box Protein O3
Forkhead Transcription Factors
medicine.disease
Catalase
Adenosine Monophosphate
Oxidative Stress
030104 developmental biology
chemistry
Animals
Newborn
Sirtuin
Immunology
biology.protein
Cardiology and Cardiovascular Medicine
Reactive Oxygen Species
Reperfusion injury
Oxidative stress
Zdroj: Basic research in cardiology. 111(2)
ISSN: 1435-1803
Popis: SIRT6, a member of the NAD(+)-dependent class III deacetylase sirtuin family, has been revealed to play important roles in promoting cellular resistance against oxidative stress. The formation of reactive oxygen species (ROS) and oxidative stress are the crucial mechanisms underlying cellular damage and dysfunction in cardiac ischemia/reperfusion (I/R) injury, but the role of SIRT6 in I/R-induced ROS and oxidative stress is poorly understood. In this study, by using heterozygous SIRT6 knockout (SIRT6(+/-)) mice and cultured neonatal cardiomyocyte models, we investigated how SIRT6 mediates oxidative stress and myocardial injury during I/R. Partial knockout (KO) of SIRT6 aggravated myocardial damage, ventricular remodeling, and oxidative stress in mice subjected to myocardial I/R, whereas restoration of SIRT6 expression by direct cardiac injection of adenoviral constructs encoding SIRT6 reversed these deleterious effects of SIRT6 KO in the ischemic heart. In addition, partial deletion of the SIRT6 gene decreased myocardial functional recovery following I/R in a Langendorff perfusion model. Similarly, the protective effects of SIRT6 were also observed in cultured cardiomyocytes following hypoxia/reoxygenation. Intriguingly, SIRT6 was noticed to up-regulate AMP/ATP and then activate the adenosine 5'-monophosphate-activated protein kinase (AMPK)-forkhead box O3α (FoxO3α) axis and further initiated the downstream antioxidant-encoding gene expression (manganese superoxide dismutase and catalase), thereby decreasing cellular levels of oxidative stress and mediating cardioprotection in the ischemic heart. These results suggest that SIRT6 protects the heart from I/R injury through FoxO3α activation in the ischemic heart in an AMP/ATP-induced AMPK-dependent way, thus upregulating antioxidants and suppressing oxidative stress.
Databáze: OpenAIRE
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