Mitochondrial dysfunction and oxidative stress in heart disease

Peoples, Jessica N; Saraf, Anita; Ghazal, Nasab; Pham, Tyler T.; Kwong, Jennifer Q.

doi:10.1038/s12276-019-0355-7

Cited by 543 publications

(420 citation statements)

References 111 publications

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“…SA-β-Gal activity was also evident 1week post-IR throughout the infarct in interstitial cells and CMs (Figure 1C and Online Figure IB). IRI is associated with increased oxidative stress, 24 and in line with this, we saw an increase in 4-HNE staining (a marker of lipid peroxidation) in the infarct zone at 72 hours following IR, with the area demonstrating the highest levels of oxidative stress also displaying the highest senescence burden (Online Figure II). In addition, we found a significant increase in the frequency of cells expressing p16 protein following IR compared with controls ( Figure 1D).…”

Section: Myocardial Infarction With Reperfusion Induces Senescence Insupporting

confidence: 79%

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Dookun

Walaszczyk

Redgrave

et al. 2020

Preprint

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Rationale:A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. We have previously shown that oxidative stress induces myocardial senescence, promoting adverse myocardial remodeling and cardiac dysfunction via the expression of a proinflammatory senescence-associated secretory phenotype (SASP). In this study we hypothesized that oxidative stress-induced senescence and SASP-mediated inflammation contribute to the pathophysiology of cardiac IRI and thus, senescence represents a novel therapeutic target. Objective:To identify if cellular senescence contributes to the pathophysiology of IRI and to investigate if pharmacological elimination of senescent cells after ischemiareperfusion can improve cardiac outcomes. Methods and Results:Using an established model of cardiac ischemia-reperfusion, we demonstrate that in young mice IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations. Additionally, we show that treatment with the senolytic drug navitoclax improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS based proteomics revealed that biological processes associated with fibrosis and inflammation, which were increased following 2 ischemia-reperfusion, were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of proinflammatory, profibrotic and antiangiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16 and fractalkine. Conclusions:Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemiareperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemiareperfusion.

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Section: Myocardial Infarction With Reperfusion Induces Senescence Insupporting

confidence: 79%

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Dookun

Walaszczyk

Redgrave

et al. 2020

Preprint

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“…The glutathione system consisting of glutathione reductase, glutathione oxidase and glutathione, maintains the concentration of O 2 • and H 2 O 2 at physiological levels necessary for tissue repair and immune defence [ 3 ]. Therefore, the ratio of oxidised and reduced glutathione indicates the redox state of a cell and may represent a valuable tool for the assessment of oxidative stress and a target for drug-based antioxidant therapies [ 4 ]. Under chronic pathological conditions, compromised or ineffective antioxidant capacity including the glutathione system results in excess ROS generation.…”

Section: Introductionmentioning

confidence: 99%

Measurement of Glutathione as a Tool for Oxidative Stress Studies by High Performance Liquid Chromatography

et al. 2020

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Background: Maintenance of the ratio of glutathione in the reduced (GSH) and oxidised (GSSG) state in cells is important in redox control, signal transduction and gene regulation, factors that are altered in many diseases. The accurate and reliable determination of GSH and GSSG simultaneously is a useful tool for oxidative stress determination. Measurement is limited primarily to the underestimation of GSH and overestimation GSSG as a result of auto-oxidation of GSH. The aim of this study was to overcome this limitation and develop, optimise and validate a reverse-phase high performance liquid chromatographic (HPLC) assay of GSH and GSSG for the determination of oxidant status in cardiac and chronic kidney diseases. Methods: Fluorescence detection of the derivative, glutathione-O-pthaldialdehyde (OPA) adduct was used. The assay was validated by measuring the stability of glutathione and glutathione-OPA adduct under conditions that could affect the reproducibility including reaction time and temperature. Linearity, concentration range, limit of detection (LOD), limit of quantification (LOQ), recovery and extraction efficiency and selectivity of the method were assessed. Results: There was excellent linearity for GSH (r2 = 0.998) and GSSG (r2 = 0.996) over concentration ranges of 0.1 µM–4 mM and 0.2 µM–0.4 mM respectively. The extraction of GSH from tissues was consistent and precise. The limit of detection for GSH and GSSG were 0.34 µM and 0.26 µM respectively whilst their limits of quantification were 1.14 µM and 0.88 µM respectively. Conclusion: These data validate a method for the simultaneous measurement of GSH and GSSG in samples extracted from biological tissues and offer a simple determination of redox status in clinical samples.

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“…A further deep analysis of the molecular processes was out of scope of this work. For example, investigations on oxidative stress due to ischemic damage and antioxidative enzymes ( Kurian et al, 2016 ; González-Montero et al, 2018 ; Peoples et al, 2019 ), as well as ATP consumption ( Casey and Arthur, 2000 ; Wu et al, 2008 ; McDougal and Dewey, 2017 ) have already been investigated and published several times; we did not intend to repeat literature data. We did not measure cardiac function recovery parameters in in vitro cell culture, albeit cardiac markers, such as troponin T could indicate a cardiac injury, and restoration of ischemic cardiac injury.…”

Section: Discussionmentioning

confidence: 99%

Comparative Effect of MSC Secretome to MSC Co-culture on Cardiomyocyte Gene Expression Under Hypoxic Conditions in vitro

Kastner

Mester-Tonczar

Winkler

et al. 2020

Front. Bioeng. Biotechnol.

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Introduction Despite major leaps in regenerative medicine, the regeneration of cardiomyocytes after ischemic conditions remains to elucidate. It is crucial to understand hypoxia induced cellular mechanisms to provide advanced treatment options, including the use of stem cell paracrine factors for myocardial regeneration. Materials and Methods In this study, the regenerative potential of hypoxic human cardiomyocytes (group Hyp-CMC) in vitro was evaluated when co-cultured with human bone-marrow derived MSC (group Hyp-CMC-MSC) or stimulated with the secretome of MSC (group Hyp-CMC-S MSC ). The secretome of normoxic MSC and CMC, and the hypoxic CMC was analyzed with a cytokine panel. Gene expression changes of HIF-1 α, proliferation marker Ki-67 and cytokinesis marker RhoA over different reoxygenation time periods of 4, 8, 24, 48, and 72 h were analyzed in comparison to normoxic CMC and MSC. Further, the proinflammatory cytokine IL-18 protein expression change, metabolic activity and proliferation was assessed in all experimental setups. Results and Conclusion HIF-1 α was persistently overexpressed in Hyp-CMC-S MSC as compared to Hyp-CMC (except at 72 h). Hyp-CMC-MSC showed a weaker HIF-1 α expression than Hyp-CMC-S MSC in most tested time points, except after 8 h. The Ki-67 expression showed the strongest upregulation in Hyp-CMC after 24 and 48 h incubation, then returned to baseline level, while a temporary increase in Ki-67 expression in Hyp-CMC-MSC at 4 and 8 h and at 48 h in Hyp-CMC-S MSC could be observed. RhoA was increased in normoxic MSCs and in Hyp-CMC-S MSC over time, but not in Hyp-CMC-MSC. A temporary increase in IL-18 protein expression was detected in Hyp-CMC-SMSC and Hyp-CMC. Our study demonstrates timely dynamic changes in expression of different ischemia and regeneration-related genes of CMCs, depending from the culture condition, with stronger expression of HIF-1 α, RhoA and IL-18 if the hypoxic CMC were subjected to the secretome of MSCs.

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Mitochondrial dysfunction and oxidative stress in heart disease

Cited by 543 publications

References 111 publications

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

Measurement of Glutathione as a Tool for Oxidative Stress Studies by High Performance Liquid Chromatography

Comparative Effect of MSC Secretome to MSC Co-culture on Cardiomyocyte Gene Expression Under Hypoxic Conditions in vitro

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