Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.

Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes.

PMP2 regulates myelin thickening and ATP production during remyelination.

It is well established that axonal Neuregulin 1 type 3 (NRG1t3) regulates developmental myelin formation as well as EGR2-dependent gene activation and lipid synthesis. However, in peripheral neuropathy disease context, elevated axonal NRG1t3 improves remyelination and myelin sheath thickness without increasing Egr2 expression or activity, and without affecting the transcriptional activity of canonical myelination genes. Surprisingly, Pmp2, encoding for a myelin fatty acid binding protein, is the only gene whose expression increases in Schwann cells following overexpression of axonal NRG1t3.

DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth.

Transient early endosome (EE)-mitochondria interactions can mediate mitochondrial iron translocation, but the associated mechanisms are still elusive. We showed that Divalent Metal Transporter 1 (DMT1) sustains mitochondrial iron translocation via EE-mitochondria interactions in triple-negative MDA-MB-231, but not in luminal A T47D breast cancer cells. DMT1 silencing increases labile iron pool (LIP) levels and activates PINK1/Parkin-dependent mitophagy in MDA-MB-231 cells.

A role for cytoglobin in regulating intracellular hydrogen peroxide and redox signals in the vasculature.

The oxidant hydrogen peroxide serves as a signaling molecule that alters many aspects of cardiovascular functions. Recent studies suggest that cytoglobin - a hemoglobin expressed in the vasculature - may promote electron transfer reactions with proposed functions in hydrogen peroxide decomposition. Here, we determined the extent to which cytoglobin regulates intracellular hydrogen peroxide and established mechanisms.

Radiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.

Radiation is associated with tissue damage and increased risk of atherosclerosis, but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that were associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known proresolving ligand, promoted swift resolution and restored efferocytosis in sublethally irradiated mice.

SDH Subunit C Regulates Muscle Oxygen Consumption and Fatigability in an Animal Model of Pulmonary Emphysema.

Patients with pulmonary emphysema often develop locomotor muscle dysfunction, which is independently associated with disability and higher mortality in that population. Muscle dysfunction entails reduced force generation capacity, which partially depends on fibers' oxidative potential, yet very little mechanistic research has focused on muscle respiration in pulmonary emphysema. Using a recently established animal model of pulmonary emphysema-driven skeletal muscle dysfunction, we found downregulation of SDHC (succinate dehydrogenase subunit C) in association with lower oxygen consumption and fatigue tolerance in locomotor muscles.

Emerging perspectives on cytoglobin, beyond NO dioxygenase and peroxidase.

Cytoglobin is an evolutionary ancient hemoglobin with poor functional annotation. Rather than constrained to penta coordination, cytoglobin's heme iron may exist either as a penta or hexacoordinated arrangement when exposed to different intracellular environments. Two cysteine residues at the surface of the protein form an intramolecular disulfide bond that regulates iron coordination, ligand binding, and peroxidase activity.

Thymine DNA glycosylase is a key regulator of CaMKIIγ expression and vascular smooth muscle phenotype.

Multifunctional Ca/calmodulin-dependent protein kinase II (CaMKII) is a multigene family with isoform-specific regulation of vascular smooth muscle (VSM) functions. In previous studies, we found that vascular injury resulted in VSM dedifferentiation and reduced expression of the CaMKIIγ isoform in medial wall VSM. Smooth muscle knockout of CaMKIIγ enhanced injury-induced VSM neointimal hyperplasia, whereas CaMKIIγ overexpression inhibited VSM proliferation and neointimal formation.

Vascular smooth muscle-MAPK14 is required for neointimal hyperplasia by suppressing VSMC differentiation and inducing proliferation and inflammation.

Injury-induced stenosis is a serious vascular complication. We previously reported that p38α (MAPK14), a redox-regulated p38MAPK family member was a negative regulator of the VSMC contractile phenotype in vitro. Here we evaluated the function of VSMC-MAPK14 in vivo in injury-induced neointima hyperplasia and the underlying mechanism using an inducible SMC-MAPK14 knockout mouse line (iSMC-MAPK14).

Vimentin expression is required for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice.

Most renal transplants ultimately fail secondary to chronic allograft nephropathy (CAN). Vimentin (vim) is a member of the intermediate filament family of proteins and has been shown to be important in the development of CAN. One of the pathways leading to chronic renal fibrosis after transplant is thought to be epithelial to mesenchymal transition (EMT).

A Brief Overview of Nitric Oxide and Reactive Oxygen Species Signaling in Hypoxia-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is characterized by increased vasoconstriction and smooth muscle cell hyperplasia driving pathological vascular remodeling of arterial vessels. In this short review, we discuss the primary source of reactive oxygen species (ROS) and nitric oxide (NO) relevant to PH and the mechanism by which dysregulation of their production contributes to PH. Specifically, hypoxia-induced PH is associated with diminished endothelial nitric oxide synthase (eNOS)-derived NO production and increased production of superoxide (O) through eNOS uncoupling and defective mitochondrial respiration.

Cytoglobin Promotes Cardiac Progenitor Cell Survival against Oxidative Stress via the Upregulation of the NFκB/iNOS Signal Pathway and Nitric Oxide Production.

Human cardiac stem/progenitor cells (hCPCs) may serve in regenerative medicine to repair the infarcted heart. However, this approach is severely limited by the poor survival of donor cells. Recent studies suggest that the mammalian globin cytoglobin (CYGB) regulates nitric oxide (NO) metabolism and cell death.

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling.

Objective: The role of hemoglobin and myoglobin in the cardiovascular system is well established, yet other globins in this context are poorly characterized. Here, we examined the expression and function of cytoglobin (CYGB) during vascular injury.

Approach And Results: We characterized CYGB content in intact vessels and primary vascular smooth muscle (VSM) cells and used 2 different vascular injury models to examine the functional significance of CYGB in vivo.

Dual Function for Mature Vascular Smooth Muscle Cells During Arteriovenous Fistula Remodeling.

Background: The arteriovenous fistula (AVF) is the preferred form of hemodialysis access for patients with chronic kidney disease. However, AVFs are associated with significant problems including high incidence of both early and late failures, usually attributed to inadequate venous arterialization and neointimal hyperplasia, respectively. Understanding the cellular basis of venous remodeling in the setting of AVF could provide targets for improving AVF patency rates.

Selective expression of TSPAN2 in vascular smooth muscle is independently regulated by TGF-β1/SMAD and myocardin/serum response factor.

Tetraspanins (TSPANs) comprise a large family of 4-transmembrane domain proteins. The importance of TSPANs in vascular smooth muscle cells (VSMCs) is unexplored. Given that TGF-β1 and myocardin (MYOCD) are potent activators for VSMC differentiation, we screened for TGF-β1 and MYOCD/serum response factor (SRF)-regulated in VSMC by using RNA-seq analyses and RNA-arrays.

MYOSLID Is a Novel Serum Response Factor-Dependent Long Noncoding RNA That Amplifies the Vascular Smooth Muscle Differentiation Program.

Objective: Long noncoding RNAs (lncRNA) represent a growing class of noncoding genes with diverse cellular functions. We previously reported on SENCR, an lncRNA that seems to support the vascular smooth muscle cell (VSMC) contractile phenotype. However, information about the VSMC-specific lncRNAs regulated by myocardin (MYOCD)/serum response factor, the master switch for VSMC differentiation, is unknown.

The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke.

The contribution of oxidative stress to ischemic brain damage is well established. Nevertheless, for unknown reasons, several clinically tested antioxidant therapies have failed to show benefits in human stroke. Based on our previous in vitro work, we hypothesized that the neuroprotective potency of antioxidants is related to their ability to limit the release of the excitotoxic amino acids glutamate and aspartate.

The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients.

Measurement of fractional nitric oxide concentration in exhaled breath (FENO) is a simple, noninvasive method to evaluate eosinophilic airway inflammation. Nitric oxide (NO) arising from peripheral small airways/alveoli (alveolar NO concentration [CalvNO]) can be estimated using multiple flow rates and a two-compartment model of the airways and alveoli. Omalizumab, a monoclonal anti-IgE antibody, is approved for the treatment of allergic asthma and also has been shown to decrease FENO levels.

Xanthine oxidase-mediated denitrosation of N-nitroso-tryptophan by superoxide and uric acid.

Recent studies indicate the formation of protein nitrosamines in vivo and tryptophan residues in proteins might represent important targets of nitrosative and oxidative stress. In the present work, we examined the mechanism by which xanthine oxidase (XO) denitrosates N-nitroso Trp residues and determined the applicability of the reactions involved to the detection of nitrosated Trp residues by tri-iodide-based chemiluminescence. We found that - in addition to superoxide - denitrosation of N-acetyl-nitroso Trp (NANT) by hypoxanthine and XO occurred via the intermediacy of uric acid.

Effects of low-dose fluticasone propionate/salmeterol combination therapy on exhaled nitric oxide and nitrite/nitrate in breath condensates from patients with mild persistent asthma.

Objective: The long-acting β2-agonist salmeterol in combination with the corticosteroid fluticasone propionate is used in clinical practice for the treatment of mild persistent asthma. Although the effect of fluticasone propionate alone in asthmatic patients is well documented, the effect of fluticasone propionate/salmeterol (FSC) combination therapy on airway inflammation and airway hyperresponsiveness (AHR) is not well characterized. Thus, we evaluated AHR, exhaled nitric oxide (FE(NO)), and nitrite and nitrate in exhaled breath condensates (EBCs) from mild persistent asthmatic patients treated with a low-dose FSC (100/50).

NADPH oxidase 4 is required for interleukin-1β-mediated activation of protein kinase Cδ and downstream activation of c-jun N-terminal kinase signaling in smooth muscle.

Reactive oxygen species (ROS) are generated in the vascular wall upon stimulation by proinflammatory cytokines and are important mediators of diverse cellular responses that occur as a result of vascular injury. Members of the NADPH oxidase (NOX) family of proteins have been identified in vascular smooth muscle (VSM) cells as important sources of ROS. In this study, we tested the hypothesis that NOX4 is a proximal mediator of IL-1β-dependent activation of PKCδ and increases IL-1β-stimulated c-Jun kinase (JNK) signaling in primary rat aortic VSM cells.

S-nitrosation: current concepts and new developments.

The S-nitrosation (also referred to as S-nitrosylation) of cysteine residues is an important post-translational protein modification that regulates protein function and cell signaling. The original research articles and reviews in this Forum cover important concepts in protein S-nitrosation and identify key developments and opportunities for progress in this area. Defining the mechanisms by which S-nitrosothiols (RSNOs) may be formed and decomposed in cells and tissues, the integration of the biological chemistry associated with nitric oxide (NO) and other derivatives such as nitrite, and the development of new methodologies merging proteomics and direct quantitation are all key issues that we believe would require detailed attention.

Selective vulnerability of synaptic signaling and metabolism to nitrosative stress.

Significance: Nitric oxide (NO) plays diverse physiological roles in the central nervous system, where it modulates neuronal communication, regulates blood flow, and contributes to the innate immune responses. In a number of brain pathologies, the excessive production of NO also leads to the formation of reactive and toxic intermediates generically termed reactive nitrogen species (RNS). RNS cause irreversible or poorly reversible damage to brain cells.