Interplay Between Calcium and Reactive Oxygen/Nitrogen Species: An Essential Paradigm for Vascular Smooth Muscle Signaling

Trebak, Mohamed; Ginnan, Roman; Singer, Harold A.; Jourd’heuil, David

doi:10.1089/ars.2009.2842

Cited by 115 publications

(90 citation statements)

References 202 publications

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“…Intriguingly, here we show that not only age-dependent RyR1 oxidation, but also cysteine nitrosylation is reduced in MCat mice. This finding is consistent with reports that uncovered the capacity of reactive nitrogen species to regulate catalase activity in skeletal muscle (31,32). Thus, catalase overexpression may down-regulate cellular levels of nitroxide free radicals, thereby impacting cysteine nitrosylation of RyR1.…”

Section: Discussionsupporting

confidence: 92%

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Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging

Umanskaya

Santulli

Xie

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

138

144

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Age-related skeletal muscle dysfunction is a leading cause of morbidity that affects up to half the population aged 80 or greater. Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca 2+ transients, decreased intracellular Ca 2+ leak and increased sarcoplasmic reticulum (SR) Ca 2+ load compared with age-matched wild type (WT) littermates. Furthermore, ryanodine receptor 1 (the sarcoplasmic reticulum Ca 2+ release channel required for skeletal muscle contraction; RyR1) from aged MCat mice was less oxidized, depleted of the channel stabilizing subunit, calstabin1, and displayed increased single channel open probability (P o ). Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca 2+ leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders.aging | skeletal muscle | exercise capacity | muscle weakness | oxidation

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Section: Discussionsupporting

confidence: 92%

“…Moreover, it has been reported that reactive nitrogen species can substantially modulate catalase and other antioxidant enzymes in skeletal muscle (8,31,32). Thus, catalase overexpression may down-regulate cellular levels of nitroxide free radicals, thereby impacting cysteine nitrosylation of RyR1.…”

Section: Resultsmentioning

confidence: 99%

Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging

Umanskaya

Santulli

Xie

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

138

144

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“…We will only briefly summarize the effects of ROS on TRPC channels as several reviews recently summarized the existing data [144][145][146][147]. One of the earliest reports on redox regulation of TRP channels by the Groschner group reports regulation of TRPC3 by the oxidant tBHP (tert-butylhydroperoxide).…”

Section: Redox Regulation Of Trpc Channelsmentioning

confidence: 99%

Redox regulation of calcium ion channels: Chemical and physiological aspects

et al. 2011

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a b s t r a c tReactive oxygen species (ROS) are increasingly recognized as second messengers in many cellular processes. While high concentrations of oxidants damage proteins, lipids and DNA, ultimately resulting in cell death, selective and reversible oxidation of key residues in proteins is a physiological mechanism that can transiently alter their activity and function. Defects in ROS producing enzymes cause disturbed immune response and disease.Changes in the intracellular free Ca 2+ concentration are key triggers for diverse cellular functions. Ca 2+ homeostasis thus needs to be precisely tuned by channels, pumps, transporters and cellular buffering systems. Alterations of these key regulatory proteins by reversible or irreversible oxidation alter the physiological outcome following cell stimulation. It is therefore necessary to understand which proteins are regulated and if this regulation is relevant in a physiological-and/or pathophysiological context. Because ROS are inherently difficult to identify and to measure, we first review basic oxygen redox chemistry and methods of ROS detection with special emphasis on electron paramagnetic resonance (EPR) spectroscopy. We then focus on the present knowledge of redox regulation of Ca 2+ permeable ion channels such as voltage-gated (CaV) Ca 2+ channels, transient receptor potential (TRP) channels and Orai channels.© 2011 Elsevier Ltd. All rights reserved. Basic redox chemistry of oxygenMany chemical processes are linked to the exchange of electrons between two or more molecular entities. The transfer of one (or more) electron(s) is associated with oxidation (loss of electron) and reduction (gain of electron) of the components. Such reactions are also known as redox reactions. The processes of reactive oxygen species (ROS) formation and elimination are exclusively of redox nature.Molecular oxygen is the precursor of all ROS. It contains two unpaired electrons in separate (antibonding) orbitals in its outer electron sphere and is thus, by definition, a radical. Radicals have at least one unpaired electron in their orbital system and usually show high reactivity; transition metal ions also may have unpaired electrons, but are not called radicals. Although having radical character, molecular oxygen is chemically rather inert (luckily!), because high * Corresponding authors at: Institut für Biophysik, Gebäude 58, Universität des Saarlandes, D-66421 Homburg/Saar, Germany. Tel.: +49 6841 1626453; fax: +49 6841 1626060.E-mail addresses: ivan.bogeski@uks.eu (I. Bogeski), barbara.niemeyer@uks.eu (B.A. Niemeyer).

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“…Although a fraction of the CAMKII pool is believed to be active, this is unlikely to account for the high basal activity observed. One explanation for this is that ROS are a potent stimulus for increased activity of CAMKII (Howe et al, 2004;Trebak et al, 2010), and the elevated levels of ROS derived from the coexpression of Nox5 may be the cause of the increased activity of WT CAMKII. Indeed, a recent study has shown that CAMKII can be directly modified by the NADPH oxidase-dependent oxidation of two methionine residues, which renders the enzyme constitutively active (Erickson et al, 2008).…”

Section: Downloaded Frommentioning

confidence: 99%

Calcium/Calmodulin-Dependent Kinase II Mediates the Phosphorylation and Activation of NADPH Oxidase 5

Pandey¹,

Gratton²,

Rafikov³

et al. 2011

Mol Pharmacol

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Excessive synthesis of reactive oxygen species contributes to the pathology of many human diseases and originates from changes in the expression and posttranslational regulation of the transmembrane NADPH oxidases (Noxes). Nox5 is a novel Nox isoform whose activity is regulated by intracellular calcium levels. We have reported that the activity and calcium-sensitivity of Nox5 can also be modulated by direct phosphorylation. However, the kinases that phosphorylate Nox5 have not been identified, and thus, the goal of this study was to determine whether calcium-activated kinases such as calcium/calmodulin-dependent kinase II (CAMKII) are involved. We found that Nox5 activity in bovine aortic endothelial cells was suppressed by two doses of the CAMKII inhibitor 2-(N-[2-hydroxyethyl])-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylamine (KN-93). In cotransfected COS-7 cells, wild-type and constitutively active CAMKII, but not a dominant-negative, robustly increased basal Nox5 activity. The ability of CAMKII to increase Nox5 activity was also observed with fixed calcium concentrations in an isolated enzyme activity assay. CAMKII did not elevate intracellular calcium or activate other Nox enzymes. In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKIIinduced increases in Nox5 activity. The ability of CAMKII␣ to phosphorylate Ser475 in intact cells was supported by the binding of Nox5 to phosphoprotein-affinity columns and via MS/MS analysis. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.

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Interplay Between Calcium and Reactive Oxygen/Nitrogen Species: An Essential Paradigm for Vascular Smooth Muscle Signaling

Cited by 115 publications

References 202 publications

Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging

Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging

Redox regulation of calcium ion channels: Chemical and physiological aspects

Calcium/Calmodulin-Dependent Kinase II Mediates the Phosphorylation and Activation of NADPH Oxidase 5

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