Redox Regulation of K Channel: Role of Thioredoxin.

Potassium channels regulate the influx and efflux of K ions in various cell types that generate and propagate action potential associated with excitation, contraction, and relaxation of various cell types. Although redox active cysteines are critically important for channel activity, the redox regulation of K channels by thioredoxin (Trx) has not been systematically reviewed. Redox regulation of K channel is now increasingly recognized as drug targets in the pathological condition of several cardiovascular disease processes.

Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK-PGC1α Signaling and Limits Oxygen Toxicity.

Administration of high concentrations of oxygen (hyperoxia) is one of few available options to treat acute hypoxemia-related respiratory failure, as seen in the current coronavirus disease (COVID-19) pandemic. Although hyperoxia can cause acute lung injury through increased production of superoxide anion (O), the choice of high-concentration oxygen administration has become a necessity in critical care. The objective of this study was to test the hypothesis that UCP2 (uncoupling protein 2) has a major function of reducing O generation in the lung in ambient air or in hyperoxia.

Chaperone-Mediated Autophagy of eNOS in Myocardial Ischemia-Reperfusion Injury.

[Figure: see text].

Nrg1β Released in Remote Ischemic Preconditioning Improves Myocardial Perfusion and Decreases Ischemia/Reperfusion Injury via ErbB2-Mediated Rescue of Endothelial Nitric Oxide Synthase and Abrogation of Trx2 Autophagy.

OBJECTIVE: Remote ischemic preconditioning (RIPC) is an intervention process where the application of multiple cycles of short ischemia/reperfusion (I/R) in a remote vascular bed provides protection against I/R injury. However, the identity of the specific RIPC factor and the mechanism by which RIPC alleviates I/R injury remains unclear. Here, we have investigated the identity and the mechanism by which the RIPC factor provides protection.

Thioredoxin deficiency exacerbates vascular dysfunction during diet-induced obesity in small mesenteric artery in mice.

Objective: Thioredoxin (Trx) is a small cellular redox protein with established antioxidant and disulfide reductase properties. We hypothesized that Trx deficiency in mice would cause increased oxidative stress with consequent redox imbalance that would exacerbate obesity-induced vascular dysfunction.

Methods: Non-transgenic (NT, C57BL/6) and dominant-negative Trx (dnTrx-Tg, low levels of redox-active protein) mice were either fed a normal diet (NC) or high fat diet plus sucrose (HFS) diet for 4 months (3-month HFD+ 1-month HFS).

Thioredoxin protects mitochondrial structure, function and biogenesis in myocardial ischemia-reperfusion via redox-dependent activation of AKT-CREB- PGC1α pathway in aged mice.

Aging is an independent risk factor for cardiovascular diseases, such as myocardial infarction due to ischemia-reperfusion injury (I/R) of the heart. Cytosolic thioredoxin (Trx) is a multifunctional redox protein which has antioxidant and protein disulfide reducing properties. We hypothesized that high levels of Trx will protect against multifactorial disease such as myocardial infarction due to I/R injury in aged mice.

Thioredoxin Decreases Anthracycline Cardiotoxicity, But Sensitizes Cancer Cell Apoptosis.

Cardiotoxicity is a major limitation for anthracycline chemotherapy although anthracyclines are potent antitumor agents. The precise mechanism underlying clinical heart failure due to anthracycline treatment is not fully understood, but is believed to be due, in part, to lipid peroxidation and the generation of free radicals by anthracycline-iron complexes. Thioredoxin (Trx) is a small redox-active antioxidant protein with potent disulfide reductase properties.

Short-duration hyperoxia causes genotoxicity in mouse lungs: protection by volatile anesthetic isoflurane.

High concentrations of oxygen (hyperoxia) are routinely used during anesthesia, and supplemental oxygen is also administered in connection with several other clinical conditions. Although prolonged hyperoxia is known to cause acute lung injury (ALI), whether short-duration hyperoxia causes lung toxicity remains unknown. We exposed mice to room air (RA or 21% O) or 60% oxygen alone or in combination with 2% isoflurane for 2 h and determined the expression of oxidative stress marker genes, DNA damage and DNA repair genes, and expression of cell cycle regulatory proteins using quantitative PCR and Western analyses.

Role of Thioredoxin in Age-Related Hypertension.

Purpose Of Review: Although the roles of oxidant stress and redox perturbations in hypertension have been the subject of several reviews, role of thioredoxin (Trx), a major cellular redox protein in age-related hypertension remains inadequately reviewed. The purpose of this review is to bring readers up-to-date with current understanding of the role of thioredoxin in age-related hypertension.

Recent Findings: Age-related hypertension is a major underlying cause of several cardiovascular disorders, and therefore, intensive management of blood pressure is indicated in most patients with cardiovascular complications.

Decreased EDHF-mediated relaxation is a major mechanism in endothelial dysfunction in resistance arteries in aged mice on prolonged high-fat sucrose diet.

High-fat sucrose (HFS) diet in aged individuals causes severe weight gain (obesity) with much higher risk of cardiovascular diseases such as hypertension or atherosclerosis. Endothelial dysfunction is a major contributor for these vascular disorders. We hypothesize that prolonged ingestion of HFS diet by aged mice would accentuate endothelial dysfunction in the small resistance arteries.

Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function.

The incidence of high blood pressure with advancing age is notably high, and it is an independent prognostic factor for the onset or progression of a variety of cardiovascular disorders. Although age-related hypertension is an established phenomenon, current treatments are only palliative but not curative. Thus, there is a critical need for a curative therapy against age-related hypertension, which could greatly decrease the incidence of cardiovascular disorders.

Thioredoxin Uses a GSH-independent Route to Deglutathionylate Endothelial Nitric-oxide Synthase and Protect against Myocardial Infarction.

Reversible glutathionylation plays a critical role in protecting protein function under conditions of oxidative stress generally and for endothelial nitric-oxide synthase (eNOS) specifically. Glutathione-dependent glutaredoxin-mediated deglutathionylation of eNOS has been shown to confer protection in a model of heart damage termed ischemia-reperfusion injury, motivating further study of eNOS deglutathionylation in general. In this report, we present evidence for an alternative mechanism of deglutathionylation.

Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells.

The mitogen-activated protein kinase kinase 4 (MKK4) is activated via phosphorylation of Ser-257 and Thr-261 by upstream MAP3Ks and activates JNK and p38 MAPKs in response to cellular stress. We show that thioredoxin (Trx), a cellular redox protein, activates MKK4 via Cys-246 and Cys-266 residues as mutation of these residues renders MKK4 insensitive to phosphorylation by MAP3Ks, TNFα, or Trx. MKK4 is activated in vitro by reduced Trx but not oxidized Trx in the absence of an upstream kinase, suggesting that autophosphorylation of this protein occurs due to reduction of Cys-246 and Cys-266 by Trx.

Thioredoxin-deficient mice, a novel phenotype sensitive to ambient air and hypersensitive to hyperoxia-induced lung injury.

Pulmonary oxygen toxicity is a major clinical problem for patients undergoing supplemental oxygen therapy. Thioredoxin (Trx) is an endogenous antioxidant protein that regenerates oxidatively inactivated proteins. We examined how Trx contributes to oxygen tolerance by creating transgenic mice with decreased levels of functional thioredoxin (dnTrx-Tg) using a dominant-negative approach.

Role of in vivo vascular redox in resistance arteries.

Vascular thiol redox state has been shown to modulate vasodilator functions in large conductance Ca2+ -activated K+ channels and other related channels. However, the role of vascular redox in small resistance arteries is unknown. To determine how in vivo modulation of thiol redox state affects small resistance arteries relaxation, we generated a transgenic mouse strain that overexpresses thioredoxin, a small redox protein (Trx-Tg), and another strain that is thioredoxin-deficient (dnTrx-Tg).

Biphasic response of checkpoint control proteins in hyperoxia: exposure to lower levels of oxygen induces genome maintenance genes in experimental baboon BPD.

Breathing high concentrations of oxygen (hyperoxia) causes lung injury and is associated with lung diseases such as bronchopulmonary dysplasia (BPD), respiratory distress syndrome and persistent pulmonary hypertension of the newborns. Hyperoxia (95-100 %O2) causes DNA damage and growth arrest of lung cells and consequently cells die by apoptosis or necrosis. Although supplemental oxygen therapy is clinically important, the level and duration of hyperoxic exposure that would allow lung cells to reenter the cell cycle remains unclear.

Hyperglycemia induces differential change in oxidative stress at gene expression and functional levels in HUVEC and HMVEC.

Background: Endothelial dysfunction precedes pathogenesis of vascular complications in diabetes. In recent years, the mechanisms of endothelial dysfunction were investigated to outline strategies for its treatment. However, the therapies for dysfunctional endothelium resulted in multiple clinical trial failures and remain elusive.

Hyperoxia decreases glycolytic capacity, glycolytic reserve and oxidative phosphorylation in MLE-12 cells and inhibits complex I and II function, but not complex IV in isolated mouse lung mitochondria.

High levels of oxygen (hyperoxia) are frequently used in critical care units and in conditions of respiratory insufficiencies in adults, as well as in infants. However, hyperoxia has been implicated in a number of pulmonary disorders including bronchopulmonary dysplasia (BPD) and adult respiratory distress syndrome (ARDS). Hyperoxia increases the generation of reactive oxygen species (ROS) in the mitochondria that could impair the function of the mitochondrial electron transport chain.

Age-dependent mitochondrial energy dynamics in the mice heart: role of superoxide dismutase-2.

The aging process alters cardiac physiology, decreases the number of cardiomyocytes and alters the energy metabolism. Mitochondrial dysfunction in aging is believed to cause these functional and phenotypic changes in the heart. Although precise understanding of alterations of mitochondrial respiration in aging is necessary to manage heart diseases in the elderly population conflicting data on the function of specific complex of electron transport chain of the heart mitochondria limits the intervention process.

c-Jun-NH2 terminal kinase (JNK)-mediates AP-1 activation by thioredoxin: phosphorylation of cJun, JunB, and Fra-1.

Thioredoxin (Trx) is a small ubiquitous protein, which has been shown to be involved in redox-dependent cellular functions. In this article, we demonstrate that the increased level of Trx induces AP-1 DNA binding in a redox-dependent manner by activating JNK subgroup of MAPKs. The majority of AP-1 DNA binding complex was found to be composed of cJun, JunB, and Fra-1.

Reactive oxygen species-independent oxidation of thioredoxin in hypoxia: inactivation of ribonucleotide reductase and redox-mediated checkpoint control.

We have investigated the role of cellular redox state on the regulation of cell cycle in hypoxia and shown that whereas cells expressing mutant thioredoxin (Trx) or a normal level of Trx undergo increased apoptosis, cells overexpressing Trx are protected against apoptosis. We show that hypoxia activates p53 and Chk1/Chk2 proteins in cells expressing normal or mutant Trx but not in cells overexpressing Trx. We also show that the activity of ribonucleotide reductase decreases in hypoxia in cells expressing redox-inactive Trx.

Differential roles of ATR and ATM in p53, Chk1, and histone H2AX phosphorylation in response to hyperoxia: ATR-dependent ATM activation.

Elevated level of oxygen (hyperoxia) is widely used in critical care units and in respiratory insufficiencies. In addition, hyperoxia has been implicated in many diseases such as bronchopulmonary dysplasia or acute respiratory distress syndrome. Although hyperoxia is known to cause DNA base modifications and strand breaks, the DNA damage response has not been adequately investigated.

Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism.

Mitogen-activated protein kinases (MAPKs) are key signaling molecules that respond to mitogenic stimulation or environmental stress, resulting in the expression of target proteins. c-Jun N-terminal kinase (JNK) and p38 MAPKs are activated by inflammatory cytokines or environmental stress. Specific p38 MAPK inhibitors, such as SB202190 or SB203580, are widely used to dissect p38 MAPK-related signal transduction mechanisms.

Caffeine inhibits UV-mediated NF-kappaB activation in A2058 melanoma cells: an ATM-PKCdelta-p38 MAPK-dependent mechanism.

Mammalian ultraviolet (UV) radiation response is a gene induction cascade activated by several transcription factors, including NF-kappaB. Although NF-kappaB is induced by UV radiation, the signal transduction mechanism remains relatively unclear. In the present study, we show that UV-induced NF-kappaB activation is mediated by the activation of Ataxia telangiecia mutated (ATM) and protein kinase C (PKC).

Thioredoxin and its role in premature newborn biology.

Thioredoxin (Trx) is a redox-active protein that has been shown to regulate various cellular processes due to its thiol-disulfide exchange reaction. It has antioxidant properties and also induces the expression of critical antioxidant enzymes such as manganese superoxide dismutase. Trx along with thioredoxin reductase and peroxiredoxins forms a complete system similar to the glutathione system, but with different and divergent functions.