Redox Regulation Of Signaling Research Articles

NRF3-mediated mitochondrial superoxide promotes cardiomyocyte apoptosis and impairs cardiac functions by suppressing Pitx2

Abstract Background Myocardial infarction (MI) elicits mitochondria reactive oxygen species (ROS) production and cardiomyocyte apoptosis. Nrf3 (Nuclear factor erythroid 2-related factor 3) has an established role in regulating redox signaling and tissue homeostasis. Herein, we aimed to uncover the exact role and potential mechanism of Nrf3 in injury-induced cardiac remodeling. Methods Global (Nrf3-KO) and cardiomyocyte-specific (NRF3△CM) Nrf3 knockout mice were subjected to MI or ischemia/reperfusion (I/R) injury, followed by functional and histopathological analysis. Primary neonatal mice (NMVMs) and rat (NRVMs) ventricular myocytes as well as cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) were used to detect the possible impact of Nrf3 on cardiomyocyte apoptosis and mitochondrial ROS production. Chromatin immunoprecipitation sequencing and immunoprecipitation–mass spectrometry analysis were used to uncover potential targets of Nrf3. MitoPQ administration and cardiomyocyte-specific AAV vector were used to further confirm the in vivo relevance of the identified signal pathways. Results Increased level of Nrf3 was observed in cardiomyocytes within border zone of infarcted human heart and murine cardiac tissues post-MI. Both global and cardiomyocyte-specific Nrf3 knockout significantly decreased injury-induced mitochondrial ROS production and cardiomyocyte apoptosis, consequently improving cardiac functions. Additionally, cardiac-specific Nrf3 overexpression reversed the cardiac phenotypes observed in Nrf3-KO mice. Functional studies showed that Nrf3 promoted NMVM, NRVM and hiPSC-CM apoptosis by increasing mitochondrial ROS production. Critically, restoring mitochondrial ROS using MitoParaquat blunted the beneficial effects of Nrf3 deletion on cardiac functions and remodeling. Mechanistically, the cardiac redox regulator paired-like homeodomain transcription factor 2 (Pitx2) was identified as one of the main target genes of Nrf3. Specifically, Nrf3 binds to Pitx2 gene promoter where it increases Pitx2 gene promoter DNA methylation through recruiting heterogeneous nuclear ribonucleoprotein K and DNA-methyltransferase 1 complex, thereby inhibiting Pitx2 expression. Importantly, cardiomyocyte-specific knockdown of Pitx2 blunted the beneficial effects of Nrf3 deletion on cardiac functions and remodeling. Conclusions Nrf3 promotes injury-induced cardiomyocyte apoptosis and deteriorates cardiac functions by increasing mitochondrial ROS production via suppressing Pitx2 expression. Targeting Nrf3-Pitx2-mitochondrial ROS signal axis could represent novel therapeutics for treating MI patients.Graphic Abstract

The molecular dynamics between reactive oxygen species (ROS), reactive nitrogen species (RNS) and phytohormones in plant's response to biotic stress.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical for plant development as well as for its stress response. They can function as signaling molecules to orchestrate a well-defined response of plants to biotic stress. These responses are further fine-tuned by phytohormones, such as salicylic acid, jasmonic acid, and ethylene, to modulate immune response. In the past decades, the intricacies of redox and phytohormonal signaling have been uncovered during plant-pathogen interactions. This review explores the dynamic interplay of these components, elucidating their roles in perceiving biotic threats and shaping the plant's defense strategy. Molecular regulators and sites of oxidative burst have been explored during pathogen perception. Further, the interplay between various components of redox and phytohormonal signaling has been explored during bacterial, fungal, viral, and nematode infections as well as during insect pest infestation. Understanding these interactions highlights gaps in the current knowledge and provides insights into engineering crop varieties with enhanced resistance to pathogens and pests. This review also highlights potential applications of manipulating regulators of redox signaling to bolster plant immunity and ensure global food security. Future research should explore regulators of these signaling pathways as potential target to develop biotic stress-tolerant crops. Further insights are also needed into roles of endophytes and host microbiome modulating host ROS and RNS pool for exploiting them as biocontrol agents imparting resistance against pathogens in plants.

Geniposidic Acid Attenuates Chronic Tubulointerstitial Nephropathy Through Regulation of the NF-ƙB/Nrf2 Pathway Via Aryl Hydrocarbon Receptor Signaling.

Renal fibrosis is an outcome of chronic kidney disease, independent of the underlying etiology. Renal fibrosis is caused primarily by oxidative stress and inflammation. We identified the components of Plantaginis semen and elucidated their anti-fibrotic and anti-inflammatory mechanisms. The renoprotective components and underlying molecular mechanisms of P. semen were investigated in rats with adenine-induced chronic tubulointerstitial nephropathy (TIN) and in idole-3-acetic acid (IAA)-stimulated NRK-52E cells. Acetate and n-butanol extracts were found to be the bioactive fractions of P. semen. A total of 65 compounds including geniposidic acid (GPA), apigenin (APG), and acteoside (ATS) were isolated and identified. Among the seven main extract components, treatment with GPA, APG, and ATS reduced the serum levels of creatinine and urea in TIN rats. Mechanistically, GPA ameliorated renal fibrosis through repressing aryl hydrocarbon receptor (AHR) signaling and regulating redox signaling including inhibiting proinflammatory nuclear factor kappa B (NF-ƙB) and its target gene products as well as activated antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream target gene products in both TIN rats and IAA-stimulated NRK-52E cells. The inhibitory effect of GPA on AHR, NF-Ƙb, and Nrf2 signaling were partially abolished in IAA-stimulated NRK-52E cells treated with CH223191 compared with untreated IAA-stimulated NRK-52E cells. These data demonstrated that GPA alleviates oxidative stress and inflammation partly by suppressing AHR signaling.

The Role of Redox Environment in Tumors.

Reactive Oxygen Species (ROS) and the redoxin system regulate the redox environment. Thus, they mediate various physiological and pathological processes involved in tumor occurrence and development by activating redox-sensitive genes and regulating redox signaling pathways, including tumor cell proliferation, migration, invasion, and various cell death types. Therefore, the mechanism underlying redox environment regulation must be clarified to accurately target this mechanism and improve the effect of tumor treatment. This review introduces redox-sensitive transcription factors and their activated downstream signaling pathways, and the application of inhibitors targeting related transcription factors in tumor therapy.

Chemical Implications of apo-8, 6' Carotendial versus Intact Lycopene on Mechanism of Enhanced Cell-cell Communication and Apoptosis Induction in Breast Cancer Cells.

Investigation on carotenoids and its cleavage products is crucial to combat the development of chronic diseases, including cancer. Therefore, this study aimed to explore the effect of lycopene oxidative products versus equivalent concentration of lycopene (LYC) on major molecular events of cancer cells (MCF-7). Primarily, LYC-oxidized products were generated chemically, then collected its rich fraction. Based on cell-based assays, the antiproliferation potency of rich fraction of chemically-oxidized lycopene (COL) identified as apo-8, 6' carotendial was compared with LYC. Interestingly, the inhibition of cell migration by COL strongly demonstrated anti-metastatic activity. Further, the increased connexin-43 expression confirms enhanced gap-junctional communication activity of COL than LYC and control. Fortunately, apo-8, 6' carotendial did not affect normal breast epithelial cells. We anticipated that, the chemical properties of apo-8, 6'-carotendial is similar and mimic a model compound acrolein (α, β-conjugated aldehyde) which is involved in Michael addition/Schiff base formation with specific amino acids and regulates redox signaling, reactive oxygen species sensing and cellular buffering. The chemistry of apo-8, 6' carotendial reveals a greater insight into the mechanism of selective inhibition of cancer cells proliferation. In this context, speculations of putative action of lycopeneoids through chemical biology approach facilitate greater insights in tandem with synthetic chemistry.

Ferroptosis-inducing compounds synergize with docetaxel to overcome chemoresistance in docetaxel-resistant non-small cell lung cancer cells

Development of resistance to therapy-induced cell death is a major hurdle in the effective treatment of advanced solid tumors. Erastin and RSL3 were originally found to induce synthetic lethality by induction of a novel form of cell death termed ferroptosis. Emerging evidence suggests that ferroptosis inducers enhance chemosensitivity of classic therapeutic agents by triggering ferroptotic cell death. In this study we evaluated the effects of erastin and RSL3 on the resistance of docetaxel, doxorubicin, and cisplatin, and revealed a mechanism whereby these ferroptosis inducers augment docetaxel efficacy in non-small cell lung cancer by regulating redox signaling to promote ferroptosis. Transcriptome analysis revealed that combination treatment modulated not only p53 signaling pathway but also immune responses and several signaling pathways including MAPK, NF-κB and PI3K/Akt. Considering that glutathione peroxidase 4 (GPX4) serves as the main effector to protect cells from ferroptosis, this study identified three novel non-covalent GPX4 inhibitors with the aid of pharmacophore-based virtual screening. The new ferroptosis-inducing compounds synergized with docetaxel to increase the cytotoxicity by promoting ferroptotic cell death in docetaxel-resistant A549/DTX cells. Collectively, the induction of ferroptosis contributed to docetaxel-induced cytotoxic effects and overcame drug resistance in A549/DTX cells. Ferroptosis has a great potential to become a new approach to attenuate resistance to some classic therapeutic drugs in cancer patients.

Aging-associated Aberrant Mitochondrial Redox Signaling, Physical Activity, and Sarcopenia.

Aging-related alteration of mitochondrial morphology, impairment in metabolic capacity, bioenergetics, and biogenesis are closely associated with loss of muscle mass and function. Mitochondrial Reactive Oxygen Species (ROS) stimulate muscular redox signaling mechanisms. Bioenergetic integrity of mitochondria and redox signaling dynamics deteriorates in aged skeletal muscle. Mitochondrial bioenergetic impairment leads to excessive ROS levels and induces the generation of defective mitochondria. Higher ROS levels may induce senescence or apoptosis. It is not a resolved issue that mitochondrial dysfunction is either the sole reason or a consequence of muscle loss (or both). However, Increasing evidence emphasizes that dysregulated mitochondrial redox signaling has a central role in age-related muscle loss. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox signaling pathways with the expression of antioxidant genes. As the aberrant redox signaling mechanisms in aging skeletal muscle become clearer, new natural and synthetic Nrf2-modulating substances and integrated daily physical activity alternatives are coming into view for preventing muscle loss in the elderly. A comprehensive understanding of the relationship between redox signaling pathways and age-related sarcopenia can help us to prevent sarcopenia and its frailty effects with an optimized exercise program as an innovative non-pharmacological therapeutic approach. A further aspect is necessary to consider both individualized physical training options and alternative Nrf2 signaling modulators. Ameliorating the redox signaling with physical activity and pharmacological interventions may help to prevent sarcopenia and its frailty effects.

The relationship of redox signaling with the risk for atherosclerosis.

Oxidative balance plays a pivotal role in physiological homeostasis, and many diseases, particularly age-related conditions, are closely associated with oxidative imbalance. While the strategic role of oxidative regulation in various diseases is well-established, the specific involvement of oxidative stress in atherosclerosis remains elusive. Atherosclerosis is a chronic inflammatory disorder characterized by plaque formation within the arteries. Alterations in the oxidative status of vascular tissues are linked to the onset, progression, and outcome of atherosclerosis. This review examines the role of redox signaling in atherosclerosis, including its impact on risk factors such as dyslipidemia, hyperglycemia, inflammation, and unhealthy lifestyle, along with dysregulation, vascular homeostasis, immune system interaction, and therapeutic considerations. Understanding redox signal transduction and the regulation of redox signaling will offer valuable insights into the pathogenesis of atherosclerosis and guide the development of novel therapeutic strategies.

Untargeted polysulfide omics analysis of alternations in polysulfide production during the germination of broccoli sprouts

Higher consumption of broccoli (Brassica oleracea var. italica) is associated with a reduced risk of cardiometabolic diseases, neurological disorders, diabetes, and cancer. Broccoli is rich in various phytochemicals, including glucosinolates, and isothiocyanates. Moreover, it has recently reported the endogenous production of polysulfides, such as cysteine hydropersulfide (CysS2H) and glutathione hydropersulfide (GS2H), in mammals including humans, and that these bioactive substances function as potent antioxidants and important regulators of redox signaling in vivo. However, few studies have focused on the endogenous polysulfide content of broccoli and the impact of germination on the polysulfide content and composition in broccoli. In this study, we investigated the alternations in polysulfide biosynthesis in broccoli during germination by performing untargeted polysulfide omics analysis and quantitative targeted polysulfide metabolomics through liquid chromatography–electrospray ionization–tandem mass spectrometry. We also performed 2,2-diphenyl-1-picrylhydrazyl radical–scavenging assay to determine the antioxidant properties of the polysulfides. The results revealed that the total polysulfide content of broccoli sprouts significantly increased during germination and growth; CysS2H and cysteine hydrotrisulfide were the predominant organic polysulfide metabolites. Furthermore, we determined that novel sulforaphane (SFN) derivatives conjugated with CysS2H and GS2H were endogenously produced in the broccoli sprouts, and the novel SFN conjugated with CysS2H exhibited a greater radical scavenging capacity than SFN and cysteine. These results suggest that the abundance of polysulfides in broccoli sprouts contribute to their health-promoting properties. Our findings have important biological implications for the development of novel pharmacological targets for the health-promoting effects of broccoli sprouts in humans.

Molecular mechanism of caloric restriction mimetics-mediated neuroprotection of age-related neurodegenerative diseases: an emerging therapeutic approach.

Aging-induced neurodegenerative diseases (NDs) are significantly increasing health problem worldwide. It has been well documented that oxidative stress is one of the potential causes of aging and age-related NDs. There are no drugs for the treatment of NDs, therefore there is an immediate necessity for the development of strategies/treatments either to prevent or cure age-related NDs. Caloric restriction (CR) and intermittent fasting have been considered as effective strategies in increasing the healthspan and lifespan, but it is difficult to adhere to these routines strictly, which has led to the development of calorie restriction mimetics (CRMs). CRMs are natural compounds that provide similar molecular and biochemical effects of CR, and activate autophagy process. CRMs have been reported to regulate redox signaling by enhancing the antioxidant defense systems through activation of the Nrf2 pathway, and inhibiting ROS generation through attenuation of mitochondrial dysfunction. Moreover, CRMs also regulate redox-sensitive signaling pathways such as the PI3K/Akt and MAPK pathways to promote neuronal cell survival. Here, we discuss the neuroprotective effects of various CRMs at molecular and cellular levels during aging of the brain. The CRMs are envisaged to become a cornerstone of the pharmaceutical arsenal against aging and age-related pathologies.

Click chemistry-based thiol redox proteomics reveals significant cysteine reduction induced by chronic ethanol consumption

In the U.S., alcohol-associated liver disease (ALD) impacts millions of people and is a major healthcare burden. While the pathology of ALD is unmistakable, the molecular mechanisms underlying ethanol hepatotoxicity are not fully understood. Hepatic ethanol metabolism is intimately linked with alterations in extracellular and intracellular metabolic processes, specifically oxidation/reduction reactions. The xenobiotic detoxification of ethanol leads to significant disruptions in glycolysis, β-oxidation, and the TCA cycle, as well as oxidative stress. Perturbation of these regulatory networks impacts the redox status of critical regulatory protein thiols throughout the cell. Integrating these key concepts, our goal was to apply a cutting-edge approach toward understanding mechanisms of ethanol metabolism in disrupting hepatic thiol redox signaling. Utilizing a chronic murine model of ALD, we applied a cysteine targeted click chemistry enrichment coupled with quantitative nano HPLC-MS/MS to assess the thiol redox proteome. Our strategy reveals that ethanol metabolism largely reduces the cysteine proteome, with 593 cysteine residues significantly reduced and 8 significantly oxidized cysteines. Ingenuity Pathway Analysis demonstrates that ethanol metabolism reduces specific cysteines throughout ethanol metabolism (Adh1, Cat, Aldh2), antioxidant pathways (Prx1, Mgst1, Gsr), as well as many other biochemical pathways. Interestingly, a sequence motif analysis of reduced cysteines showed a correlation for hydrophilic, charged amino acids lysine or glutamic acid nearby. Further research is needed to determine how a reduced cysteine proteome impacts individual protein activity across these protein targets and pathways. Additionally, understanding how a complex array of cysteine-targeted post-translational modifications (e.g., S–NO, S-GSH, S–OH) are integrated to regulate redox signaling and control throughout the cell is key to the development of redox-centric therapeutic agents targeted to ameliorate the progression of ALD.

Reactive Sulfur Species Omics Analysis in the Brain Tissue of the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whereby oxidative stress augmentation results in mitochondrial dysfunction and cell death by apoptosis. Emerging evidence indicates that reactive sulfur species (RSS), such as glutathione hydropersulfide (GSSH), is endogenously produced, functions as potent antioxidants, and regulate redox signaling through the formation of protein polysulfides. However, the relationship between RSS and AD pathogenesis is not fully understood. In this study, we analyzed endogenous RSS production in the brain tissue of a familial AD model (5xFAD) mouse using multiple RSS-omics approaches. Memory impairment, increased amyloid plaques, and neuroinflammation have been confirmed in 5xFAD mice. Quantitative RSS omics analysis revealed that the total polysulfide content was significantly decreased in the brains of 5xFAD mice, whereas there was no significant difference in the levels of glutathione, GSSH, or hydrogen sulfide between wild-type and 5xFAD mice. In contrast, a significant decline in the protein polysulfide status was observed in the brains of 5xFAD mice, suggesting that RSS production and subsequent redox signaling might be altered during the onset and progression of AD. Our findings have important implications for understanding the significance of RSS in the development of preventive and therapeutic strategies for AD.

H2S regulates redox signaling downstream of cardiac β-adrenergic receptors in a G6PD-dependent manner

Stimulating β-adrenergic receptors (β-AR) culminates in pathological hypertrophy – a condition underlying multiple cardiovascular diseases (CVDs). The ensuing signal transduction network appears to involve mutually communicating phosphorylation-cascades and redox signaling modules, although the regulators of redox signaling processes remain largely unknown. We previously showed that H2S-induced Glucose-6-phosphate dehydrogenase (G6PD) activity is critical for suppressing cardiac hypertrophy in response to adrenergic stimulation. Here, we extended our findings and identified novel H2S-dependent pathways constraining β-AR-induced pathological hypertrophy. We demonstrated that H2S regulated early redox signal transduction processes – including suppression of cue-dependent production of reactive oxygen species (ROS) and oxidation of cysteine thiols (R-SOH) on critical signaling intermediates (including AKT1/2/3 & ERK1/2). Consistently, the maintenance of intracellular levels of H2S dampened the transcriptional signature associated with pathological hypertrophy upon β-AR-stimulation, as demonstrated by RNA-seq analysis. We further prove that H2S remodels cell metabolism by promoting G6PD activity to enforce changes in the redox state that favor physiological cardiomyocyte growth over pathological hypertrophy. Thus, our data suggest that G6PD is an effector of H2S-mediated suppression of pathological hypertrophy and that the accumulation of ROS in the G6PD-deficient background can drive maladaptive remodeling. Our study reveals an adaptive role for H2S relevant to basic and translational studies. Identifying adaptive signaling mediators of the β-AR-induced hypertrophy may reveal new therapeutic targets and routes for CVD therapy optimization.

BIOLOGICAL ROLE OF THIOREDOXIN-MEDIATED INTRACELLULAR SIGNALING DURING PHYSIOLOGICAL AGING (LITERATURE REVIEW)

Thioredoxin is a low molecular weight protein found in all organisms. It is associated with the regulation of numerous cellular processes such as gene expression, antioxidant response, apoptosis, and proliferation. In humans, thioredoxin is represented by two functionally different forms, Trx1 and Trx2. The review contains the results of studies on the biological role of thioredoxin, with special attention paid to its role in the regulation of the physiological aging process. The aim of the study was to study the available literature sources that publish materials on the biological role of thioredoxin, paying special attention to its significance in the regulation of the physiological aging process. Materials and methods. To achieve the goal of the study, methods of analysis, generalization, comparison and systematization of these publications of domestic and foreign authors were used. Results. The main function of the thioredoxin-dependent system is antioxidant activity. Trx and glutathione (GSH) play a central role in counteracting oxidative stress. In addition to its antioxidant properties, Trx, unlike other antioxidant enzymes, plays an important role in maintaining the redox state of cells and in regulating redox signaling. There is a lot of evidence in the literature that shows the stimulating effect of thioredoxin on tissue proliferation. The Trx system is hypothesized to promote the development and spread of cancer through various mechanisms, including inhibition of apoptosis, promotion of cell growth, and maintenance of angiogenesis. There is also evidence of an important role of the thioredoxin system in aging. Conclusions. Thus, there are data on the participation of the thioredoxin system in the processes of aging, carcinogenesis, regulation of proliferation, and apoptosis. However, the role of thioredoxin in age-related changes in organs has not been studied enough, so additional studies are needed.

Computational and Retrosynthetic Investigation of Isoxazole‐Bearing Chalcones as Antioxidant Activate Compounds

AbstractPeroxiredoxin 5 (1HD2) is an antioxidant enzyme that catalyzes the decrease of peroxide, and act as a regulator of Redox signaling. It is a potential target for working on new antioxidants. 3D‐QSAR method was applied to a set of isoxazoles by using the comparative analysis of molecular fields (CoMFA and CoMSIA). Five new drug candidates (Pr1–Pr5) have been proposed. The study of the interactions between the drug candidate and antioxidant receptor 1HD2 was done by molecular docking. The results of the ADME (Absorption, Distribution, Metabolism, and Excretion) showed that these drug candidates are orally bioavailable and have high gastrointestinal absorption and good permeability. Molecular dynamics was used at 100 ns to study the stability of the MA‐1HD2 and Pr5‐1HD2 complexes obtained after molecular docking. Using the retrosynthesis approach, we have proposed a pathway for synthesizing the drug candidates. This study provides useful information on the antioxidant activity of isoxazole‐based compounds.

Recent advances in the application and biological mechanism of silicon nitride osteogenic properties: a review.

Silicon nitride, an emerging bioceramic material, is highly sought after in the biomedical industry due to its osteogenesis-promoting properties, which are a result of its unique surface chemistry and excellent mechanical properties. Currently, it is used in clinics as an orthopedic implant material. The osteogenesis-promoting properties of silicon nitride are manifested in its contribution to the formation of a local osteogenic microenvironment, wherein silicon nitride and its hydrolysis products influence osteogenesis by modulating the biological behaviors of the constituents of the osteogenic microenvironment. In particular, silicon nitride regulates redox signaling, cellular autophagy, glycolysis, and bone mineralization in cells involved in bone formation via several mechanisms. Moreover, it may also promote osteogenesis by influencing immune regulation and angiogenesis. In addition, the wettability, surface morphology, and charge of silicon nitride play crucial roles in regulating its osteogenesis-promoting properties. However, as a bioceramic material, the molding process of silicon nitride needs to be optimized, and its osteogenic mechanism must be further investigated. Herein, we summarize the impact of the molding process of silicon nitride on its osteogenic properties and clinical applications. In addition, the mechanisms of silicon nitride in promoting osteogenesis are discussed, followed by a summary of the current gaps in silicon nitride mechanism research. This review, therefore, aims to provide novel ideas for the future development and applications of silicon nitride.

The antioxidant glutathione.

Reduced glutathione (GSH) is an essential non-enzymatic antioxidant in mammalian cells. GSH can act directly as an antioxidant to protect cells against free radicals and pro-oxidants, and as a cofactor for antioxidant and detoxification enzymes such as glutathione peroxidases, glutathione S-transferases, and glyoxalases. Glutathione peroxidases detoxify peroxides by a reaction that is coupled to GSH oxidation to glutathione disulfide (GSSG). GSSG is converted back to GSH by glutathione reductase and cofactor NADPH. GSH can regenerate vitamin E following detoxification reactions of vitamin E with lipid peroxyl radicals (LOO). GSH is a cofactor for GST during detoxification of electrophilic substances and xenobiotics. Dicarbonyl stress induced by methylglyoxal and glyoxal is alleviated by glyoxalase enzymes and GSH. GSH regulates redox signaling through reversible oxidation of critical protein cysteine residues by S-glutathionylation. GSH is involved in other cellular processes such as protein folding, protecting protein thiols from oxidation and crosslinking, degradation of proteins with disulfide bonds, cell cycle regulation and proliferation, ascorbate metabolism, apoptosis and ferroptosis.

Zinc transporter 8 haploinsufficiency protects against beta cell dysfunction in type 1 diabetes by increasing mitochondrial respiration

ObjectiveZinc transporter 8 (ZnT8) is a major humoral target in human type 1 diabetes (T1D). Polymorphic variants of Slc30A8, which encodes ZnT8, are also associated with protection from type 2 diabetes (T2D). The current study examined whether ZnT8 might play a role beyond simply being a target of autoimmunity in the pathophysiology of T1D. MethodsThe phenotypes of NOD mice with complete or partial global loss of ZnT8 were determined using a combination of disease incidence, histological, transcriptomic, and metabolic analyses. ResultsUnexpectedly, while complete loss of ZnT8 accelerated spontaneous T1D, heterozygosity was partially protective. In vivo and in vitro studies of ZnT8 deficient NOD.SCID mice suggested that the accelerated disease was due to more rampant autoimmunity. Conversely, beta cells in heterozygous animals uniquely displayed increased mitochondrial fitness under mild proinflammatory conditions. ConclusionsIn pancreatic beta cells and immune cell populations, Zn2+ plays a key role as a regulator of redox signaling and as an independent secondary messenger. Importantly, Zn2+ also plays a major role in maintaining mitochondrial homeostasis. Our results suggest that regulating mitochondrial fitness by altering intra-islet zinc homeostasis may provide a novel mechanism to modulate T1D pathophysiology.

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also regulate redox signaling in many cell types with essential functions in the cardiovascular system. Research over the past couple of decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes regulate oxidative stress and compartmentalize intracellular signaling in endothelial cells, smooth muscle cells, macrophages, cardiomyocytes, fibroblasts, and other cell types. NOX2 and NOX4, for example, regulate distinct redox signaling mechanisms in cardiac myocytes pertinent to the onset and progression of cardiac hypertrophy and heart failure. Heart failure with preserved ejection fraction (HFpEF), which accounts for at least half of all heart failure cases and has few effective treatments to date, is classically associated with ventricular diastolic dysfunction, i.e., defects in ventricular relaxation and/or filling. However, HFpEF afflicts multiple organ systems and is associated with systemic pathologies including inflammation, oxidative stress, arterial stiffening, cardiac fibrosis, and renal, adipose tissue, and skeletal muscle dysfunction. Basic science studies and clinical data suggest a role for systemic and myocardial oxidative stress in HFpEF, and evidence from animal models demonstrates the critical functions of NOX enzymes in diastolic function and several HFpEF-associated comorbidities. Here, we discuss the roles of NOX enzymes in cardiovascular cells that are pertinent to the development and progression of diastolic dysfunction and HFpEF and outline potential clinical implications.

Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death.

Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.