Reiko Matsui

Boston University | BU · Department of Medicine

Liver fibrosis is a sign of non-alcoholic fatty liver disease progression towards steatohepatitis (NASH) and cirrhosis and is accelerated by aging. Glutaredoxin-1 (Glrx) controls redox signaling by reversing protein S-glutathionylation, induced by oxidative stress, and its deletion causes fatty liver in mice. Although Glrx regulates various pathway...

Aims S-glutathionylation is a reversible oxidative modification of protein cysteines that plays a critical role in redox signaling. Glutaredoxin-1 (Glrx), a glutathione-specific thioltransferase, removes protein S-glutathionylation. Glrx, though a cytosolic protein, can activate a nuclear protein Sirtuin-1 (SirT1) by removing its S-glutathionylatio...

Cardiovascular diseases are the leading cause of death worldwide, and as rates continue to increase, discovering mechanisms and therapeutic targets become increasingly important. An underlying cause of most cardiovascular diseases is believed to be excess reactive oxygen or nitrogen species. Glutathione, the most abundant cellular antioxidant, play...

Reactive oxygen species (ROS) increase during adipogenesis and in obesity. Oxidants react with cysteine residues of proteins to form glutathione (GSH) adducts, S-glutathionylation, that are selectively removed by glutaredoxin-1 (Glrx). We have previously reported that Glrx knockout mice had increased protein S-glutathionylation and developed obesit...

Significance: Over the past several years, oxidative post-translational modifications of protein cysteines have been recognized for their critical roles in physiology and pathophysiology. Cells have harnessed thiol modifications involving both oxidative and reductive steps for signaling and protein processing. One of these stages requires oxidation...

Glutaredoxin-1 (Glrx) is a small cytosolic enzyme that removes S-glutathionylation, glutathione adducts of protein cysteine residues, thus modulating redox signaling and gene transcription. Although Glrx up-regulation prevented endothelial cell (EC) migration and global Glrx transgenic mice had impaired ischemic vascularization, the effects of cell...

Delivering and expressing a gene of interest in cells or living animals has become a pivotal technique in biomedical research and gene therapy. Among viral delivery systems, adeno-associated viruses (AAVs) are relatively safe and demonstrate high gene transfer efficiency, low immunogenicity, stable long-term expression, and selective tissue tropism...

Sirtuin-1 (SirT1) catalyzes NAD⁺-dependent protein lysine deacetylation and is a critical regulator of energy and lipid metabolism, mitochondrial biogenesis, apoptosis, and senescence. Activation of SirT1 mitigates metabolic perturbations associated with diabetes and obesity. Pharmacologic molecules, cellular redox, and nutritional states can regul...

Interleukin (IL)-33 is an interleukin-1 like cytokine that enhances Th2 responses and mediates mucosal immunity and allergic inflammation but the mechanism regulating endogenous IL-33 production are still under investigation. In macrophages, lipopolysaccharide (LPS) administration resulted in marked induction of IL-33 mRNA that was blunted in macro...

CRA-induced IL-33 in RAW cells. Different doses of CRA (0–80 μg/ml) was tested to examine IL-33 and Glrx induction in RAW cells with siControl or siGlrx RNA. (PDF)

F4/80 staining on mouse peritoneal macrophages. Adhered peritoneal cells were fixed and stained with anti-mouse F4/80 antibody (red) and Hoechst (blue). (PDF)

CRA-induced Glrx mRNA in WT and IL-33 KO mouse macrophages. CRA (Cockroach antigen 100 μg/ml) or PBS was added in isolated mouse macrophages from WT and IL-33 KO mice. After 6 hours RNA was isolated from cells by Trizol and Glrx expression was examined (n = 3–4 wells). (PDF)

IL-33-induced IL-33 protein is shifted in non-reduced condition. LPS (100ng/ml) or IL-33 (50 ng/ml) was added in RAW cells for 6 hours, and cellular proteins were analyzed in reduced and non-reduced gel. (PDF)

Background Glutaredoxin 1 (Grx1), an antioxidant enzyme, plays an important role in protecting cells from oxidative stress and apoptosis, events associated with myocardial remodeling and failure. Transgenic mice with cardiac-specific overexpression of Gαq develop a dilated cardiomyopathy. In the present study, we examined the effects of Grx1 on myo...

Glutaredoxin-1 (Glrx) removes glutathione (GSH) adducts of protein thiols (S-glutathionylated protein) and controls cellular signaling and gene transcription. Human lung fibrosis decreases Glrx protein expression, and conversely, Glrx administration attenuates bleomycin-induced lung fibrosis in mice. We previously showed that Glrx knockout (KO) mic...

Glutaredoxin-1 (Glrx) is a cytosolic enzyme that reverses glutathione (GSH) adducts of protein thiols generated through oxidative post-translational modifications. GSH-adducts regulate cellular signaling and transcription factors. We previously found that after femoral artery ligation Glrx knockout mice improved blood flow recovery in relation to a...

Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death1-3. Oxidative stress is believed to be critical in this disease pathogenesis4-6, although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modificatio...

Objective Glutaredoxin-1 (Glrx) is a cytosolic enzyme which removes glutathione (GSH) adducts of protein thiols (S-glutathionylation), and controls protein functions including cellular signaling and gene transcription. We previously showed that Glrx knockout middle-aged mice developed liver steatosis and Glrx replenishment by viral gene transfer su...

Mechanisms for the lack of efficacy of anti-angiogenic strategies for cancer have not been elucidated. We previously demonstrated that up-regulated glutaredoxin-1 (Glrx) inhibited endothelial cell (EC) angiogenic properties. Glrx is a small cytosolic enzyme which reverses glutathione adducts on protein thiols. Global Glrx transgenic mice had impair...

Glutathione (GSH) adducts formation on protein thiols (S-glutathionylation), an oxidative post-translational modification, is reversed by glutaredoxin-1 (Glrx). We previously found that Glrx transgenic mice showed impaired blood flow recovery after femoral artery ligation (Murdoch 2014), while this ischemic revascularization was improved in Glrx kn...

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the l...

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the l...

Introduction High soluble Flt1 (sFlt1) is pivotal in the development of ‘preeclampsia phenotype’ of hypertension and proteinuria. Disruption of endogenous protective pathways and increased oxidative stress are hallmarks.of preeclampsia. Yet the underlying molecular mechanisms remains unclear. During high oxidative stress, thiols on key proteins are...

Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice...

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the l...

Aims: Nonalcoholic fatty liver (NAFL) is a common liver disease associated with metabolic syndrome, obesity, and diabetes that is rising in prevalence worldwide. Various molecular perturbations of key regulators and enzymes in hepatic lipid metabolism cause NAFL. However, redox regulation through glutathione (GSH) adducts in NAFL remains largely e...

Supplementary material

Background: Oxidative stress is implicated in increased vascular permeability associated with metabolic disorders, but the underlying redox mechanism is poorly defined. S-glutathionylation, a stable adduct of glutathione with protein sulfhydryl, is a reversible oxidative modification of protein and is emerging as an important redox signaling paradi...

Aims: Neuroinflammation and redox dysfunction are recognized factors in Parkinson’s disease (PD) pathogenesis; and diabetes is implicated as a potentially predisposing condition. Remarkably, upregulation of glutaredoxin-1 (Grx1) is implicated in regulation of inflammatory responses in various disease contexts, including diabetes. Here we investigat...

Significance Glutathione (GSH)-protein adducts are oxidative posttranslational modifications that are reversed by glutaredoxin-1 (Glrx). We show that ischemia-induced oxidants promote revascularization through GSH adducts on hypoxia-inducible factor (HIF)-1α, an angiogenic transcriptional factor. GSH adducts on Cys ⁵²⁰ stabilize HIF-1α protein, and...

Antioxidants are expected to improve cardiovascular disease (CVD) by eliminating oxidative stress, but clinical trials have not shown promising results in chronic CVD. Animal studies have revealed that reactive oxygen species (ROS) exacerbate acute CVDs in which high levels of ROS are observed. However, ROS are also necessary for angiogenesis after...

The endothelium produces and responds to reactive oxygen and nitrogen species (RONS), providing important redox regulation to the cardiovascular system in physiology and disease. In no other situation are RONS more critical than in the response to tissue ischemia. Here, tissue healing requires growth factor-mediated angiogenesis that is in part dep...

Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential c...

IPA predicted multiple protein networks associated with oxidative changes caused by catalase overexpression. The 11 ‘node’ proteins are highlighted in grey. Legend to network analysis: enzyme (diamond), transmembrane receptor (vertical oval), transcriptional regulator (horizontal oval), phosphatase (triangle), transporter (trapezoid), kinase (trian...

Cardiac mitochondrial maximal and uncoupled oxygen consumption were similar in both groups. (A) Maximal (State III) and uncoupled (oligomycin 2μM) (State IV) complex I substrate-driven oxygen consumption rate; (B) Maximal (State III) and uncoupled (oligomycin 2 μM) (State IV) complex II substrate-driven oxygen consumption rate. Data represents mean...

Multiplexed quantitation of reversible cysteine oxidation in Cat Tg and WT mice. (A) TMT-switch labeling strategy. To determine the total available (free and reducible) cysteines, half of each left ventricle was completely reduced and labeled with iodoTMT; to label only reversibly oxidized cysteines, all free cysteines were blocked by IAM during ly...

Validation of TMT-tagged peptides. (A) Peptide frequency histogram of the coefficient of variation (CV) for changes in total available cysteine thiols (●), reversibly oxidized cysteine thiols (□) and their occupancy (∆). (B) Distribution of TMT-tagged peptides. A total of 2264 peptides with modifications were detected by LC-MS/MS analysis, of which...

Complete list of proteins with a change in thiol oxidation in Cat Tg vs. WT. Accession number, gene ID, sites of modification and peptide sequences were retrieved from the Uniprot knowledgebase. Fold changes in Cat Tg vs. WT, were calculated from ratio of reporter ions for changes in total available cysteine as (m/z 129)/(m/z 127), reversibly oxidi...

Proteins with a change in thiol occupancy by >2-fold in Cat Tg vs. WT mice. Accession number, gene ID, sites of modification and peptide sequences were retrieved from the Uniprot knowledgebase. Fold changes in Cat Tg vs. WT, were calculated from ratio of reporter ions for changes in total available cysteine as (m/z 129)/(m/z 127), reversibly oxidiz...

Proteins involved in five canonical pathways predicted in IPA, with a change in thiol occupancy by >1.3-fold in Cat Tg vs. WT. Accession number, gene ID, sites of modification and peptide sequences were retrieved from the Uniprot knowledgebase. Fold changes in Cat Tg vs. WT, were calculated from ratio of reporter ions for changes in total available...

S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflamma...

Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes. Glrx overexpression inhibits VEGF-induced endothelial cell (EC) migration. The aim was to inve...

Sirtuin-1 (SirT1), a member of the NAD+-dependent class III histone deacetylase family, is inactivated in vitro by oxidation of critical cysteine thiols. In a model of metabolic syndrome, SirT1 activation attenuated apoptosis of hepatocytes and improved liver function including lipid metabolism. We show in SirT1-overexpressing HepG2 cells that oxid...

Reactive oxygen and nitrogen species contributing to homeostatic regulation and the pathogenesis of various cardiovascular diseases, including atherosclerosis, hypertension, endothelial dysfunction, and cardiac hypertrophy, is well established. The ability of oxidant species to mediate such effects is in part dependent on their ability to induce sp...

Characteristic morphological and molecular alterations such as vessel wall thickening and reduction of nitric oxide occur in the aging vasculature leading to the gradual loss of vascular homeostasis. Consequently, the risk of developing acute and chronic cardiovascular diseases increases with age. Current research of the underlying molecular mechan...

Glutaredoxin-1 (Glrx) is a thioltransferase that regulates protein S-glutathiolation. To elucidate the role of endogenous Glrx in cardiovascular disease, Glrx knockout (KO) mice were infused with angiotensin II (Ang II) for 6days. After Ang II infusion, body weight and blood pressure were similar between WT and Glrx KO mice. However, compared to WT...

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway that is a major source of cellular NADPH. The purpose of this study was to examine whether G6PD deficiency affects vascular oxidants and atherosclerosis in high-fat fed apolipoprotein (apo) E(-/-) mice. G6PD-mutant mice whose G6PD activity was 20% of normal we...

Glucose-6-phosphate dehydrogenase (G6PD) regulates production of the reduced form of NADPH through the pentose phosphate pathway. G6PD may therefore affect superoxide anion production via vascular NADPH oxidase, which is key in mediating the vascular response to angiotensin II (Ang II). We determined the hypertensive and vascular hypertrophic respo...

Hypertension caused by angiotensin II is characterized by an increase in tissue oxidant stress as evidenced by increased quantities of reactive oxygen and nitrogen species. Manganese superoxide dismutase (MnSOD) is a key mitochondrial antioxidant enzyme that is inactivated in conditions of oxidant stress by reacting with peroxynitrite to form 3-nit...

Antioxidants improve endothelial function in hypercholesterolemia (HC); however, whether this includes improvement of the vascular smooth muscle response to NO is unknown. NO relaxes arteries, in part, by stimulating Ca(2+) uptake via sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) in aortic smooth muscle, and HC impairs SERCA function and the re...

Background: Hypercholesterolemia (HC) impairs acetylcholine-induced relaxation but has little effect on that caused by the NO donor sodium nitroprusside (SNP), suggesting that acetylcholine releases less NO from the endothelium in HC. The relaxation to authentic NO gas, however, is also impaired in HC aortic smooth muscle, indicating an abnormal s...

Fibroblast growth factors (FGFs) play important roles in diverse aspects of animal development including mammalian lung epithelial cell proliferation, differentiation, and branching morphogenesis. We developed an in vitro lung epithelial cell culture system to study functions and mechanisms of FGFs in regulating growth and differentiation of primar...

Fibroblast growth factors (FGFs) play important roles in diverse aspects of animal development including mammalian lung epithelial cell proliferation, differentiation, and branching morphogenesis. We developed an in vitro lung epithelial cell culture system to study functions and mechanisms of FGFs in regulating growth and differentiation of primar...

This study examined the effects of beta-D-xyloside (an inhibitor of proteoglycan synthesis) and cis-4-hydroxyl-L-proline (an inhibitor of collagen synthesis) on branching morphogenesis in cultures of fetal rat lung. Lungs from day 15 gestation were incubated for 4 days in (1) the control medium (Dulbecco's Modified Eagle Medium + 10% Fetal Bovine S...

Alveolar type II (T2) cells synthesise matrix proteins such as type IV collagen and fibronectin. In contrast, a fetal rat T2 cell line has been shown to synthesise type I and III collagen as well as type IV collagen. To study regulation of collagen production in T2 cells, neonatal T2 cells immortalised by adenoviral 12SE1A gene transfer were used....

Compensatory lung growth after pneumonectomy is a well established phenomenon in young humans and experimental animals. To date, the cellular initiating and/or regulatory factor(s) responsible for this growth response have yet to be established. We have studied changes in lung content and activity of calmodulin, a calcium-dependent regulatory prote...

We studied the pattern of airways branching in the fetal rat lung in vitro. Lung primordia of gestational ages 13, 14, and 15 days were allowed to grow in culture to a gestational age equivalent to 21 days. The first generation airways appear by a single new bud (monopodial budding) from the left main airway (lateral appearing before the medial). T...