Papers by Narayana Anilkumar
JACC. Basic to translational science, 2017
The reactive oxygen species-generating enzyme NADPH oxidase 4 (Nox4) is up-regulated in the heart... more The reactive oxygen species-generating enzyme NADPH oxidase 4 (Nox4) is up-regulated in the heart after myocardial infarction (MI). Mice with cardiomyocyte-targeted Nox4 overexpression (TG) displayed increased macrophages in the heart at baseline, with skewing toward an M2 phenotype compared with wild-type controls (WT). After MI, TG mice had a higher proportion of M2 macrophages along with higher survival, decreased cardiac remodeling, and better contractile function than wild-type mice. The post-MI increase in cardiac matrix metalloproteinase-2 activity was substantially blunted in TG mice. These results indicate that cardiomyocyte Nox4 modulates macrophage polarization toward an M2 phenotype, resulting in improved post-MI survival and remodeling, likely through the attenuation of cardiac matrix metalloproteinase-2 activity.
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Journal of Cell Science
Thrombospondin-1 (TSP-1) and the highly related protein thrombospondin-2 (TSP-2) are trimeric ext... more Thrombospondin-1 (TSP-1) and the highly related protein thrombospondin-2 (TSP-2) are trimeric extracellular molecules that have complex roles in wound healing, angiogenesis and matrix organisation. At the cellular level, TSP-1 supports cell adhesion and migration by the organisation of fascin spike cytoskeletal structures. To define the molecular requirements for assembly of fascin spikes by thrombospondins, we developed a panel of recombinant protein units of TSP-1 and TSP-2; these were designed according to the domain boundaries and included matched monomeric and trimeric units. These proteins were tested for their effects on cell attachment and fascin spike organisation using C2C12 skeletal myoblasts and vascular smooth muscle cells. In monomeric units, cell attachment activity was localised to the type 1 repeats or type 3 repeats/C-terminal globule, and both regions need to be present in the same molecule for maximal activity. On a molar basis, cell-attachment activities with mo...
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Cytometry, 1996
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The EMBO Journal, 2003
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BioEssays, 2002
The fascins are a structurally unique and evolutionarily conserved group of actin cross-linking p... more The fascins are a structurally unique and evolutionarily conserved group of actin cross-linking proteins. Fascins function in the organisation of two major forms of actin-based structures: dynamic, cortical cell protrusions and cytoplasmic microfilament bundles. The cortical structures, which include filopodia, spikes, lamellipodial ribs, oocyte microvilli and the dendrites of dendritic cells, have roles in cell-matrix adhesion, cell interactions and cell migration, whereas the cytoplasmic actin bundles appear to participate in cell architecture. We discuss the current understanding of the cellular mechanisms that regulate the binding of fascin to actin and how these processes contribute to the organisation or disassembly of cell protrusions. Although the in vivo roles of fascin have been studied principally in Drosophila, several human diseases are associated with inherited or acquired alterations in the expression of fascins. Strategies to modulate fascin-containing protrusions and thereby cell adhesive and migratory behaviour could have potential for therapeutic intervention in these conditions. The supplementary material referred to in this section can be found at http://www.interscience.wiley.com/jpages/0265-9247/suppmat/2002/v24.350.html
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ALGAE, 2009
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Circulation, Oct 28, 2008
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Circulation, Nov 23, 2010
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J Cell Biochem, 1996
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Circulation, Nov 23, 2010
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Frontiers in Bioscience, Feb 1, 2009
Adaptation of the heart to intrinsic and external stress involves complex modifications at the mo... more Adaptation of the heart to intrinsic and external stress involves complex modifications at the molecular and cellular level that lead to tissue remodeling and functional compensation or failure depending upon the nature, intensity and chronicity of the stress. Signaling mechanisms mediated by reactive oxygen species (ROS) are now known to play important roles in many aspects of this complex process. In particular, the tightly regulated generation of ROS by NADPH oxidases appears especially important in key signaling events that drive the development of cardiomyocyte hypertrophy, fibrosis, extracellular matrix remodelling and cell apoptosis. This review discusses the signaling pathways modulated by ROS during the development of cardiac remodelling and failure with a particular emphasis on the role of NADPH oxidases.
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Circulation, Oct 31, 2006
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The EMBO journal, Jan 7, 2016
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis b... more Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine-threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4-regulated pathway robustly enhances cell surv...
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Free radical biology & medicine, Jan 13, 2015
Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic deto... more Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic detoxification of xenobiotics and other environmental toxins. Hepatic glutathione is also a major systemic store for other organs and thus impacts on pathologies such as Alzheimer's disease, Sickle Cell Anaemia and chronic diseases associated with aging. Glutathione levels are determined in part by the availability of cysteine, generated from homocysteine through the transsulfuration pathway. The partitioning of homocysteine between remethylation and transsulfuration pathways is known to be subject to redox-dependent regulation, but the underlying mechanisms are not known. An association between plasma Hcy and a single nucleotide polymorphism within the NADPH oxidase 4 locus led us to investigate the involvement of this reactive oxygen species- generating enzyme in homocysteine metabolism. Here we demonstrate that NADPH oxidase 4 ablation in mice results in increased flux of homocysteine...
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Free Radical Biology and Medicine, 2015
Laminar shear stress (LSS) triggers signals that ultimately result in atheroprotection and vasodi... more Laminar shear stress (LSS) triggers signals that ultimately result in atheroprotection and vasodilatation. Early responses are related to the activation of specific signaling cascades. We investigated the participation of redox-mediated modifications and in particular the role of hydrogen peroxide (H2O2) in the sulfenylation of redox-sensitive phosphatases. Exposure of vascular endothelial cells to short periods of LSS (12dyn/cm(2)) resulted in the generation of superoxide radical anion as detected by the formation of 2-hydroxyethidium by HPLC and its subsequent conversion to H2O2, which was corroborated by the increase in the fluorescence of the specific peroxide sensor HyPer. By using biotinylated dimedone we detected increased total protein sulfenylation in the bovine proteome, which was dependent on NADPH oxidase 4 (NOX4)-mediated generation of peroxide. Mass spectrometry analysis allowed us to identify the phosphatase SHP2 as a protein susceptible to sulfenylation under LSS. Given the dependence of FAK activity on SHP2 function, we explored the role of FAK under LSS conditions. FAK activation and subsequent endothelial NO synthase (eNOS) phosphorylation were promoted by LSS and both processes were dependent on NOX4, as demonstrated in lung endothelial cells isolated from NOX4-null mice. These results support the idea that LSS elicits redox-sensitive signal transduction responses involving NOX4-dependent generation of hydrogen peroxide, SHP2 sulfenylation, and ulterior FAK-mediated eNOS activation.
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Circulation
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Scientific Reports, 2012
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Papers by Narayana Anilkumar