SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Liu, Ban; Che, Wenliang; Zheng, Changzhu; Liu, Weijing; Wen, Jing; Fu, Hua; Tang, Kai; Zhang, Jinying; Xu, Yawei

doi:10.1159/000354505

Cited by 78 publications

(52 citation statements)

References 38 publications

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“…The second study showed that Sirt5 levels are decreased in H9c2 cells following 12 hours hydrogen peroxide treatment and that siRNA knockdown of Sirt5 reduced apoptosis following hydrogen peroxide treatment. [30]. To better clarify the role of Sirt5 in a model of ischemia and reperfusion we subjected Langendorff perfused hearts from Sirt5 −/− mice and their wild type littermates to ischemia and reperfusion and assessed recovery of function and infarct size.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the cardiac succinylome and its role in ischemia–reperfusion injury

Boylston

Sun

Chen

et al. 2015

Journal of Molecular and Cellular Cardiology

136

123

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Succinylation refers to modification of lysine residues with succinyl groups donated by succinyl-CoA. Sirtuin5 (Sirt5) is a mitochondrial NAD+-dependent deacylase that catalyzes the removal of succinyl groups from proteins. Sirt5 and protein succinylation are conserved across species, suggesting functional importance of the modification. Sirt5 loss impacts liver metabolism but the role of succinylation in the heart has not been explored. We combined affinity enrichment with proteomics and mass spectrometry to analyze total succinylated lysine content of mitochondria isolated from WT and Sirt5−/− mouse hearts. We identified 887 succinylated lysine residues in 184 proteins. 44 peptides (5 proteins) occurred uniquely in WT samples, 289 (46 proteins) in Sirt5−/− samples, and 554 (133 proteins) were common to both groups. The 46 unique proteins in Sirt5−/− heart participate in metabolic processes such as fatty acid β-oxidation (Eci2) and branched chain amino acid catabolism, and include respiratory chain proteins (Ndufa7, 12, 13, Dhsa). We performed label-free analysis of the peptides common to WT and Sirt5−/− hearts. 16 peptides from 9 proteins were significantly increased in Sirt5−/− by at least 30%. The adenine nucleotide transporter 1 showed the highest increase in succinylation in Sirt5−/− (108.4 fold). The data indicate that succinylation is widespread in the heart and enriched in metabolic pathways. We examined whether the loss of Sirt5 would impact ischemia-reperfusion (I/R) injury and we found an increase in infarct size in Sirt5−/− hearts compared to WT littermates (68.5+/− 1.1% Sirt5−/− vs 39.6+/− 6.8% WT) following 20 minutes of ischemia and 90 minutes reperfusion. We further demonstrate that I/R injury in Sirt5−/− heart is restored to WT levels by pretreatment with dimethyl malonate, a competitive inhibitor of succinate dehydrogenase (SDH), implicating alteration in SDH activity as causative of the injury.

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Section: Discussionmentioning

confidence: 99%

Characterization of the cardiac succinylome and its role in ischemia–reperfusion injury

Boylston

Sun

Chen

et al. 2015

Journal of Molecular and Cellular Cardiology

136

123

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“…Activation of mitochondria mediated apoptotic pathway could induce the cardiomyocytes apoptosis [18]. Inhibiton of ROS production could protect cardiomyocytes against oxidative stress [19].…”

Section: Discussionmentioning

confidence: 99%

Thrombopoietin Protects Cardiomyocytes from Iron-Overload Induced Oxidative Stress and Mitochondrial Injury

Chan

et al. 2015

Cell Physiol Biochem

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Background/Aims: Thalassaemia accompanied with iron-overload is common in Hong Kong. Iron-overload induced cardiomyopathy is the commonest cause of morbidity and mortality in patients with β-thalassaemia. Chronic iron-overload due to blood transfusion can cause cardiac failure. Decreased antioxidant defence and increased ROS production may lead to oxidative stress and cell injury. Iron-overload may lead to heart tissue damage through lipid peroxidation in response to oxidative stress, and a great diversity of toxic aldehydes are formed when lipid hydroperoxides break down in heart and plasma. Methods: Iron entry into embryonic heart H9C2 cells was determined by calcein assay using a fluorometer. Reactive oxygen species (ROS) production in cells treated with FeCl₃ or thrombopoietin (TPO) was monitored by using the fluorescent probe H₂DCFDA. Changes in mitochondrial membrane potential of H9C2 cells were quantified by using flow cytometry. Results: We demonstrated that iron induced oxidative stress and apoptosis in cardiomyocytes, and that iron increased ROS production and reduced cell viability in a dose-dependent manner. Iron treatment increased the proportion of cells with JC-1 monomers, indicating a trend of drop in the mitochondrial membrane potential. TPO exerted a cardio-protective effect on iron-induced apoptosis. Conclusions: These findings suggest that iron-overload leads to the generation of ROS and further induces apoptosis in cardiomyocytes via mitochondrial pathways. TPO might exert a protective effect on iron-overload induced apoptosis via inhibiting oxidative stress and suppressing the mitochondrial pathways in cardiomyocytes.

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“…Due to its availability to modulate hypoxia-induced cardiomyocyte viability and apoptosis, Sirt-4 activation can be beneficial in ischemic heart disease. Sirt-5 is known to be downregulated by oxidative stress in cardiomyocytes and to act as a safeguard against ROS by reducing ROS-induced cell death [29]. …”

Section: Mitochondrial Sirtuinsmentioning

confidence: 99%

Mitochondrial redox status as a target for cardiovascular disease

Walters

Amos

Ray

et al. 2016

Current Opinion in Pharmacology

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Mitochondria are a major player in cellular energetics, oxidative stress and programmed cell death. Mitochondrial dynamics regulates and integrates these functions. Mitochondrial dysfunction is involved in cardiac hypertrophy, hypertension and myocardial ischemia/reperfusion injury. Reactive oxygen species generation is modulated by the fusion-fission pathway as well as key proteins such as sirtuins that act as metabolic sensors of cellular energetics. Mitochondrial redox status has thus become a good target for therapy against cardiovascular diseases. Recently, there is an influx of studies garnered towards assessing the beneficial effects of mitochondrial targeted antioxidants, drugs modulating the fusion-fission proteins, sirtuins, and other mitochondrial processes as potential cardio-protecting agents.

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SIRT5: A Safeguard Against Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Cited by 78 publications

References 38 publications

Characterization of the cardiac succinylome and its role in ischemia–reperfusion injury

Characterization of the cardiac succinylome and its role in ischemia–reperfusion injury

Thrombopoietin Protects Cardiomyocytes from Iron-Overload Induced Oxidative Stress and Mitochondrial Injury

Mitochondrial redox status as a target for cardiovascular disease

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