Redox signaling in cardiac myocytes

Santos, Cláudia Y.; Anilkumar, Narayana; Zhang, Min; Brewer, Alison C.; Shah, Ajay M.

doi:10.1016/j.freeradbiomed.2011.01.003

Cited by 285 publications

(280 citation statements)

References 260 publications

(255 reference statements)

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“…Cytosolic NADPH is predominantly provided by Glc-6-PD or by the cytosolic isoforms IDH1 and ME1. H 2 O 2 , but not O 2 . , can diffuse through membranes.…”

Section: Compartmentalized Expression Of Redox Sensors-mentioning

confidence: 91%

“…), which is dismutated to H 2 O 2 by mitochondrial superoxide dismutase (SOD2). Similarly, SOD1 catalyzes O 2 . conversion to H 2 O 2 in the cytoplasm.…”

Section: Compartmentalized Expression Of Redox Sensors-mentioning

confidence: 99%

“…Reactive oxygen species (ROS) 2 serve as both signaling molecules and destructive agents, requiring cells to finely regulate their levels. Antioxidant enzymes catalyze ROS conversion directly via an active-site metal ion (e.g.…”

mentioning

confidence: 99%

“…superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1)(2)(3)(4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.…”

mentioning

confidence: 99%

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Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Dey

Sidor

O’Rourke

2016

Journal of Biological Chemistry

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Oxidative stress arises from an imbalance in the production and scavenging rates of reactive oxygen species (ROS) and is a key factor in the pathophysiology of cardiovascular disease and aging. The presence of parallel pathways and multiple intracellular compartments, each having its own ROS sources and antioxidant enzymes, complicates the determination of the most important regulatory nodes of the redox network. Here we quantified ROS dynamics within specific intracellular compartments in the cytosol and mitochondria and determined which scavenging enzymes exert the most control over antioxidant fluxes in H9c2 cardiac myoblasts. We used novel targeted viral gene transfer vectors expressing redox-sensitive GFP fused to sensor domains to measure H 2 O 2 or oxidized glutathione. Using genetic manipulation in heart-derived H9c2 cells, we explored the contribution of specific antioxidant enzymes to ROS scavenging and glutathione redox potential within each intracellular compartment. Our findings reveal that antioxidant flux is strongly dependent on mitochondrial substrate catabolism, with availability of NADPH as a major rate-controlling step. Moreover, ROS scavenging by mitochondria significantly contributes to cytoplasmic ROS handling. The findings provide fundamental information about the control of ROS scavenging by the redox network and suggest novel interventions for circumventing oxidative stress in cardiac cells. Reactive oxygen species (ROS)2 serve as both signaling molecules and destructive agents, requiring cells to finely regulate their levels. Antioxidant enzymes catalyze ROS conversion directly via an active-site metal ion (e.g. superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1-4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.In cardiac myocytes, ROS are a byproduct of mitochondrial electron transport (5) and are also produced by extramitochondrial sources, including NADPH oxidase (1), uncoupled nitric oxide synthase (6), xanthine oxidase (7), and monoamine oxidase (8, 9). Both mitochondrial and extramitochondrial sources have been implicated in cardiac disorders including heart failure, myocardial ischemia, and arrhythmias. The dynamics and steady-state levels of ROS in local intracellular domains are determined by the rates of free radical generation and scavenging. Failure to scavenge free radicals via antioxidant fluxes can trigger a vicious cycle of dysfunction, leading to death (10). Recent studies have demonstrated that antioxidant enzymes targeted to the mitochondria, but not the cytoplasm, protect agai...

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“…Cytosolic NADPH is predominantly provided by Glc-6-PD or by the cytosolic isoforms IDH1 and ME1. H 2 O 2 , but not O 2 . , can diffuse through membranes.…”

Section: Compartmentalized Expression Of Redox Sensors-mentioning

confidence: 91%

“…), which is dismutated to H 2 O 2 by mitochondrial superoxide dismutase (SOD2). Similarly, SOD1 catalyzes O 2 . conversion to H 2 O 2 in the cytoplasm.…”

Section: Compartmentalized Expression Of Redox Sensors-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Dey

Sidor

O’Rourke

2016

Journal of Biological Chemistry

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“…In the cardiovascular field, studies using transgenic and knock-out mouse models implicated TS in the protection against cardiac hypertrophy and ischemia/reperfusion (I/R) damages (12),which is a major cardiac stress triggering a complex REDOX response (32,43,54,58). Loss of TrxR1 expression in cardiomyocytes (cTrxR1 -/ -) had a tendency to render those cells more sensitive to I/R.…”

Section: Introductionmentioning

confidence: 99%

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

Mustafi

Grose

Zhang

et al. 2014

Antioxidants & Redox Signaling

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Aims: The human mutation R120G in the aB-crystallin (CRYAB) causes a multisystemic disease that is characterized by hypertrophic cardiomyopathy and cytoplasmic protein aggregates. In transgenic mice, human R120GCRYAB (hR120GTg) expression in heart sequentially modifies the REDOX status, in part by the activation of the nuclear factor, erythroid derived 2, like 2 (Nrf2). Thioredoxin system (TS) components are NRF2 target genes, so it could be hypothesized that TS was affected in hR120GTg mice. Results: Transgenic hearts overexpressed thioredoxin 1 (Trx1), which was identified by isotope coded affinity tag-mass spectrometry, among hundreds of peptides displaying an increased reduced/oxidized ratio. Coupled to this higher level of reduced cysteines, the activity of thioredoxin reductase 1 (TrxR1) was augmented by 2.5-fold. Combining mutiple experimental approaches, the enzymatic regulation of TrxR1 by a histone deacetylase 3 (HDAC3)-dependent level of acetylation was confirmed. In vitro and in vivo functional tests established that TrxR1 activity is required to mitigate aggregate development, and this could be mediated by Bcl-2-associated athanogene 3 (BAG3) as a potential TS substrate. Innovation and Conclusions: This study uncovers the compartmentalized changes and the involvement of TS in the cardiac stress response elicited by misfolded proteins such as R120GCRYAB. Our work suggests that R120GCRYAB triggers a defensive pathway acting through the newly identified interacting partners HDAC3, TrxR1, and BAG3 to counter aggregate growth. Therefore, those interactors may function as modifier genes contributing to the variable onset and expressivity of such human diseases. Furthermore, our work underscores the potential organismal effects of pharmacological interventions targeting TS and HDAC.

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Cardiac Ischemia and Reperfusion

Murugesan¹,

Zweíer²

2013

Molecular Basis of Oxidative Stress

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Redox signaling in cardiac myocytes

Cited by 285 publications

References 260 publications

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

Cardiac Ischemia and Reperfusion

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