Metformin ameliorates hypoxia/reoxygenation-induced cardiomyocyte apoptosis based on the SIRT3 signaling pathway

Du, Yanyan; Zhang, Jingjing; Fang, Fang; Wei, Xiqing; Zhang, Hongsheng; Tan, Hua-Qiao; Zhang, Jinguo

doi:10.1016/j.gene.2017.05.018

Cited by 20 publications

(10 citation statements)

References 21 publications

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“…Our results suggest two pathways involved in pathological accumulation of free radicals through (i) loss of functional expression of mt‐mRNA translation products for OXPHOS and (ii) downregulation of GPx proteins for H 2 O 2 clearance. An alternative approach to combat excess ROS may be utilizing alternative pharmaceuticals, which could indirectly reduce myocardial ROS 85 …”

Section: Resultsmentioning

confidence: 99%

“…An alternative approach to combat excess ROS may be utilizing alternative pharmaceuticals, which could indirectly reduce myocardial ROS. 85 FIGURE 6 Media from Lewis lung carcinoma (LLC) cancer cells contribute to greater reactive oxygen species (ROS) and reduced oxidative capacity. H9c2 cells were treated with a combination of LLC control media (CM; LCM) and 2 μM of the mitochondrial targeted antioxidant (MitoT) for 2 h and ROS assessed using MitoSOX (A,B) or similar treatment for 24 h analysing cellular bioenergetic flux analysis (C) to analyse oxygen consumption rates at (D) basal and (E) maximal (that is FCCP-stimulated) rates, or calculated reserve rates (F).…”

Section: Mitochondrial Antioxidants Mitigate Effects Of Tumour-associated Factors On Cardiomyocyte Reactive Oxygen Species Production Andmentioning

confidence: 99%

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Cancer‐induced cardiac atrophy adversely affects myocardial redox state and mitochondrial oxidative characteristics

Lee

Brown

Rosa‐Caldwell

et al. 2020

JCSM Rapid Communications

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Background Cachexia presents in 80% of advanced cancer patients; however, cardiac atrophy in cachectic patients receives little attention. This cardiomyopathy contributes to increased occurrence of adverse cardiac events compared with age‐matched population norms. Research on cardiac atrophy has focused on remodelling; however, alterations in metabolic properties may be a primary contributor. The purpose of the study is to determine how cancer‐induced cardiac atrophy alters mitochondrial turnover, mitochondrial mRNA translation machinery, and in vitro oxidative characteristics. Methods Lewis lung carcinoma (LLC) tumours were implanted in C57BL6/J mice and grown for 28 days to induce cardiac atrophy. Endogenous metabolic species and markers of mitochondrial function were assessed. H9c2 cardiomyocytes were cultured in LLC‐conditioned media with (out) the antioxidant MitoTempo. Cells were analysed for reactive oxygen species (ROS), oxidative capacity, and hypoxic resistance. Results LLC heart weights were ~10% lower than controls. LLC hearts demonstrated ~15% lower optical redox ratio [flavin adenine dinucleotide (FAD)/FAD + nicotinamide adenine dinucleotide hydrogen (NADH)] compared with phosphate‐buffered saline controls. When compared with phosphate‐buffered saline, LLC hearts showed ~50% greater Cytochrome‐C oxidase subunit 4 (COX‐IV) and Voltage‐dependent anion channel (VDAC), attributed to ~50% lower mitophagy markers. mt‐mRNA translation machinery was elevated similarly to markers of mitochondrial content. Mitochondrial DNA‐encoded Cytb was ~30% lower in LLC hearts. ROS scavengers GPx‐3 and GPx‐7 were ~50% lower in LLC hearts. Treatment of cardiomyocytes with LLC‐conditioned media resulted in higher ROS (25%), lower oxygen consumption rates (10% at basal and 75% at maximal), and greater susceptibility to hypoxia (~25%), which was reversed by MitoTempo. Conclusions These results substantiate metabolic cardiotoxic effects attributable to tumour‐associated factors and provide insight into interactions between mitochondrial mRNA translation, ROS mitigation, oxidative capacity, and hypoxia resistance.

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Section: Resultsmentioning

confidence: 99%

Section: Mitochondrial Antioxidants Mitigate Effects Of Tumour-associated Factors On Cardiomyocyte Reactive Oxygen Species Production Andmentioning

confidence: 99%

Cancer‐induced cardiac atrophy adversely affects myocardial redox state and mitochondrial oxidative characteristics

Lee

Brown

Rosa‐Caldwell

et al. 2020

JCSM Rapid Communications

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“…During stress, SIRT3, another member of this family, has similar effects. Results of Du et al (2017) demonstrated that SIRT3 decreases the level of ROS and apoptosis in myocardial cells, and so has cardioprotective effects ( Du et al, 2017 ). In agreement with other results ( Nakhaee et al, 2019 , 2020 ), our findings revealed that exercise improves cardiac dysfunction caused by smoking, probably by increasing the levels of SIRT1 and SIRT3.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Sirtuins and Klotho in Cardioprotective Effects of Exercise Training Against Waterpipe Tobacco Smoking-Induced Heart Dysfunction

et al. 2021

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Despite its negative effect on the cardiovascular system, waterpipe smoking (WPS) is currently popular worldwide, especially among youth. This study investigated the effects of moderate endurance exercise on heart function of rats exposed to WPS and its possible mechanism. The animals were randomly divided into four groups: control group (CTL), the exercise group (Ex) which trained for 8 weeks, the waterpipe tobacco smoking group (S) exposed to smoke inhalation (30 min per day, 5 days each week, for 8 weeks), and the group that did exercise training and received waterpipe tobacco smoke inhalation together (Ex + S). One day after the last session of Ex and WPS, cardiac pressures and functional indices were recorded and calculated. The levels of SIRT1, SIRT3, Klotho, Bax, and Bcl-2 in the serum and heart, the expression of phosphorylated GSK3β of heart tissue, and cardiac histopathological changes were assessed. WPS reduced systolic pressure, +dP/dt max, -dP/dt max, and heart contractility indices (P < 0.001 vs. CTL) and increased cardiac tissue lesions (P < 0.05 vs. CTL) and end diastolic pressure and Tau index (P < 0.001 vs. CTL) of the left ventricle. Exercise training normalized the left ventricular end diastolic pressure, +dP/dt max, and contractility index. Also, exercise improved the levels of SIRT1, SIRT3, Klotho, and Bcl-2 and reduced Bax level in the heart. The findings showed that WPS causes left ventricular dysfunction. Moderate exercise prevented WPS-induced heart dysfunction partly through its anti-apoptotic features and activation of the sirtuins and Klotho pathways.

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“…Several studies also showed that metformin exerts cardioprotective effects by reducing myocardial cell apoptosis, which are key features of cardiac function (29). In an experimental study, metformin significantly repressed the number of TUNEL-positive myocytes (30). It has been hypothesized that the inhibition of the pathways associated with cell apoptosis may be a potential therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Treatment with metformin prevents myocardial ischemia-reperfusion injury via STEAP4 signaling pathway

Luo¹

2019

Anatol J Cardiol

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Objective: The aim of the present study was to investigate the underlying mechanism of metformin in reducing myocardial apoptosis and improving mitochondrial function in rats and H9c2 cells subjected to myocardial ischemia–reperfusion (I/R) or hypoxia–reoxygenation (H/R) injuries, respectively. Methods: Following pretreatment with metformin, male Sprague–Dawley rats were used to establish an I/R model in vivo. Serum creatinine kinase-MB and cardiac troponin T levels were examined by enzyme-linked immunosorbent assay. Infarct size and apoptosis were measured by triphenyl tetrazolium chloride staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Pathological changes were evaluated by hematoxylin and eosin staining. H9c2 cells were used to establish an H/R model in vitro . Cell apoptosis and mitochondrial membrane potential (MMP) were examined by flow cytometry and Rhodamine 123. The expression levels of six-transmembrane epithelial antigen of prostate 4 (STEAP4), B-cell lymphoma 2, Bcl-2-associated X protein, and glyceraldehyde 3-phosphate dehydrogenase in both myocardial tissues and H9c2 cells were determined by western blotting. Results: We found that metformin decreased infarct size, increased STEAP4 expression, mitigated myocardial apoptosis, and increased MMP when the models were subjected to H/R or I/R injuries. However, STEAP4 knockdown significantly abrogated the beneficial effect of metformin. Conclusion: We further demonstrated the protective effect of metformin on cardiomyocytes, which might be at least partly attributable to the upregulation of STEAP4. Therefore, STEAP4 might be a new target to decrease apoptosis and rescue mitochondrial function in myocardial I/R injury.

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Metformin ameliorates hypoxia/reoxygenation-induced cardiomyocyte apoptosis based on the SIRT3 signaling pathway

Cited by 20 publications

References 21 publications

Cancer‐induced cardiac atrophy adversely affects myocardial redox state and mitochondrial oxidative characteristics

Cancer‐induced cardiac atrophy adversely affects myocardial redox state and mitochondrial oxidative characteristics

Involvement of Sirtuins and Klotho in Cardioprotective Effects of Exercise Training Against Waterpipe Tobacco Smoking-Induced Heart Dysfunction

Treatment with metformin prevents myocardial ischemia-reperfusion injury via STEAP4 signaling pathway

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