Evidence map›Paper›PMID 24903103›Full record

ArticleCirculation research2014

OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase.

Deepesh Pandey, Anil Bhunia, Young Jun Oh, Fumin Chang, Yehudit Bergman, Jae Hyung Kim, Janna Serbo, Tatiana N Boronina, Robert N Cole, Jennifer Van Eyk and 3 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
50citing papers in PubMed, 1 pooled it
4.7field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

50 citing papers in PubMed, 1 synthesis or guideline pooled it, 91 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 1 institution in 1 country.

Deepesh PandeyFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Anil BhuniaFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Young Jun OhFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Fumin ChangFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Yehudit BergmanFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Jae Hyung KimFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Janna SerboFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Tatiana N BoroninaFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Robert N ColeFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Jennifer Van EykFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Alan T RemaleyFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Dan E BerkowitzFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.).
Lewis H RomerFrom the Department of Anesthesiology and Critical Care Medicine (D.P., A.B., Y.J.O., F.C., Y.B., J.H.K., J.S., D.E.B., L.H.R.), Biomedical Engineering (J.S., D.E.B., L.H.R.), and Cell Biology, Pediatrics, Center for Cell Dynamics (L.H.R.), Mass Spectrometry and Proteomics Facility (T.N.B., R.N.C.), and Departments of Medicine and Biological Chemistry (J.V.E.), Johns Hopkins University School of Medicine, Baltimore, MD; and Lipoprotein Metabolism Section, Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A.T.R.). LRomer@jhmi.edu.
Johns Hopkins University · US

Funding

Use Of Animal Models To Study Lipid Genes That Modulate AtherosclerosisZIAHL002058 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI REMALEY, ALAN THOMAS · 2009 to 2019
$14.3M
Use Of Animal Models To Study Lipid Genes That Modulate AtherosclerosisZ01HL002058 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI REMALEY, ALAN THOMAS · 1996 to 2008
$5.8M
Arginase II, A Novel Target in AtherosclerosisR01HL089668 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI BERKOWITZ, DAN E, ROMER, LEWIS H · 2011 to 2014
$1.6M
Request for Zeiss LSM 510 MP Multiphoton Imaging SystemS10RR024550 · NCRR · JOHNS HOPKINS UNIVERSITY · PI KUO, SCOT CHARLES · 2008 to 2008
$500k
Intramural NIH HHS Z01 HL002058NCRR NIH HHS S10 RR024550NCRR NIH HHS S10RR024550NHLBI NIH HHS HL089668NHLBI NIH HHS R01 HL089668
6 · The paper itself

Abstract

rationaleIncreased arginase activity contributes to endothelial dysfunction by competition for l-arginine substrate and reciprocal regulation of nitric oxide synthase (NOS). The rapid increase in arginase activity in human aortic endothelial cells exposed to oxidized low-density lipoprotein (OxLDL) is consistent with post-translational modification or subcellular trafficking.

objectiveTo test the hypotheses that OxLDL triggers reverse translocation of mitochondrial arginase 2 (Arg2) to cytosol and Arg2 activation, and that this process is dependent on mitochondrial processing peptidase, lectin-like OxLDL receptor-1 receptor, and rho kinase. METHODS AND

resultsOxLDL-triggered translocation of Arg2 from mitochondria to cytosol in human aortic endothelial cells and in murine aortic intima with a concomitant rise in arginase activity. All of these changes were abolished by inhibition of mitochondrial processing peptidase or by its siRNA-mediated knockdown. Rho kinase inhibition and the absence of the lectin-like OxLDL receptor-1 in knockout mice also ablated translocation. Aminoterminal sequencing of Arg2 revealed 2 candidate mitochondrial targeting sequences, and deletion of either of these confined Arg2 to the cytoplasm. Inhibitors of mitochondrial processing peptidase or lectin-like OxLDL receptor-1 knockout attenuated OxLDL-mediated decrements in endothelial-specific NO production and increases in superoxide generation. Finally, Arg2(-/-) mice bred on an ApoE(-/-) background showed reduced plaque load, reduced reactive oxygen species production, enhanced NO, and improved endothelial function when compared with ApoE(-/-) controls.

conclusionsThese data demonstrate dual distribution of Arg2, a protein with an unambiguous mitochondrial targeting sequence, in mammalian cells, and its reverse translocation to cytoplasm by alterations in the extracellular milieu. This novel molecular mechanism drives OxLDL-mediated arginase activation, endothelial NOS uncoupling, endothelial dysfunction, and atherogenesis.

Indexed as

Amino Acid SequenceAnimalsAortaAortic DiseasesApolipoproteins EArginaseAtherosclerosisCells, CulturedCytosolDisease Models, AnimalEndothelial CellsEnzyme ActivationHumansLipoproteins, LDLMaleMetalloendopeptidasesApolipoproteins EARG2 protein, humanArg2 protein, mouseArginaseLipoproteins, LDLMetalloendopeptidasesMitochondrial Processing PeptidaseOlr1 protein, mouseoxidized low density lipoproteinProtein Kinase Inhibitorsrho-Associated KinasesScavenger Receptors, Class Earginaseatherosclerosismitochondriamitochondrial processing peptidasenitric oxide synthase type IIIoxidized low density lipoprotein

Identifiers

PMID24903103
PMCPMC8760889
OpenAlexW2121498936

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Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.