ArticleArteriosclerosis, thrombosis, and vascular biology2018
Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus.
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Article in Arteriosclerosis, thrombosis, and vascular biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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39citing papers in PubMed, 1 pooled it
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39 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Changes in corneal biomechanics in patients with diabetes mellitus: a systematic review and meta-analysis.Acta diabetologica · 2020Pooled it
- Loss of the Coronary Artery Disease Risk GeneCirculation · 2026Article
- Balancing cellular copper levels via the post-translational regulation of copper transport.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Review
- Copper dysregulation in cardiometabolic disease: copper deficiency versus cuproptosis.Apoptosis : an international journal on programmed cell death · 2026Review
- Antioxidant Potential ofMolecules (Basel, Switzerland) · 2026Article
- Copper Homeostasis and Cuproptosis As Potential Intervention Strategy in Atherosclerosis.Journal of cardiovascular translational research · 2025Review
- Exercise-Induced SOD3/HCirculation research · 2025Article
- A new mechanism of high-altitude adaptation reducing myocardium infarction: inhibiting inflammation-induced ubiquitin degradation of BKBasic research in cardiology · 2025Article
- The role of dysregulated copper metabolism in diabetes and its complications: a review.Frontiers in endocrinology · 2025Review
- EndothelialCurrent diabetes reviews · 2025Review
- Deciphering the Role of Copper Homeostasis in Atherosclerosis: From Molecular Mechanisms to Therapeutic Targets.International journal of molecular sciences · 2024Review
- The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus.Molecules (Basel, Switzerland) · 2024Review
- Sleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes.Nature communications · 2024Article
- Emerging insights into cuproptosis and copper metabolism: implications for age-related diseases and potential therapeutic strategies.Frontiers in aging neuroscience · 2024Review
- Association of SLC11A1 polymorphisms with anthropometric and biochemical parameters describing Type 2 Diabetes Mellitus.Scientific reports · 2023Article
- Toward a hypothesis-free understanding of how phosphorylation dynamically impacts protein turnover.Proteomics · 2023Article
- ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury.International journal of molecular sciences · 2023Article
- Identification of core cuprotosis-correlated biomarkers in abdominal aortic aneurysm immune microenvironment based on bioinformatics.Frontiers in immunology · 2023Article
- Preparation of Ultra-Small Copper Nanoparticles-Loaded Self-Healing Hydrogels with Antibacterial, Inflammation-Suppressing and Angiogenesis-Enhancing Properties for Promoting Diabetic Wound Healing.International journal of nanomedicine · 2023Article
- Role of Oxidative Stress in the Pathogenesis of Atherothrombotic Diseases.Antioxidants (Basel, Switzerland) · 2022Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Varadarajan SudhaharFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Mustafa Nazir OkurFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Zsolt BagiFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
John P O'BryanFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Nissim HayFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Ayako MakinoFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Vijay S PatelFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Shane A PhillipsFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
David SteppFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Masuko Ushio-FukaiFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.).
Tohru FukaiFrom the Vascular Biology Center (V.S., Z.B., D.S., M.U.-F., T.F.), Department of Pharmacology and Toxicology (V.S., T.F.), Department of Medicine (Cardiology) (Z.B., M.U.-F.), and Department of Surgery (V.S.P.), Medical College of Georgia at Augusta University; Departments of Medicine (Cardiology) and Pharmacology (V.S., T.F.), Department of Pharmacology (M.N.O., J.P.O., M.U.-F.), Center for Cardiovascular Research (V.S., J.P.O., M.U.-F., T.F.), Department of Physical Therapy (S.A.P.), and Department of Biochemistry and Molecular Genetics (N.H.), University of Illinois at Chicago; Department of Medicine and Physiology, University of Arizona, Tucson (A.M.), Jesse Brown Veterans Affairs Medical Center, Chicago, IL (V.S., T.F.); and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., T.F.). tfukai@augusta.edu.
Jesse Brown VA Medical Center · USUniversity of Illinois Chicago · USUniversity of Arizona · US
Funding
Probing RAS-mediated Signaling with Monobody InhibitorsR01CA212608 · NCI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI SHOHEI KOIDE, John P O'Bryan · 2017 to 2026
$5.8MVascular Extracellular Superoxide Dismutase ModulationR01HL070187 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI FUKAI, TOHRU · 2002 to 2017
$4.2MImproving Blood Pressure & Vascular risk with resistance exercise in African AmericansR01HL130513 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI PHILLIPS, SHANE A · 2016 to 2020
$3.5MRedox Regulation of Cu Importer CTR1 in AngiogenesisR01HL147550 · NHLBI · AUGUSTA UNIVERSITY · PI FUKAI, TOHRU, USHIO-FUKAI, MASUKO · 2020 to 2023
$3.3MCopper transport protein and inflammatory angiogenesisR01HL116976 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI FUKAI, TOHRU, USHIO-FUKAI, MASUKO · 2013 to 2016
$2.9MCu Transporting ATPase and Diabetic Vascular ComplicationsR01HL133613 · NHLBI · AUGUSTA UNIVERSITY · PI FUKAI, TOHRU, USHIO-FUKAI, MASUKO · 2017 to 2020
$2.7MNotch1/miR-322 Axis in Stem Cell Mediated Vascular RepairR01HL134354 · NHLBI · AUGUSTA UNIVERSITY · PI ASHRAF, MUHAMMAD, TANG, YAO LIANG · 2016 to 2020
$2.5MReactive Oxygen Species and Endothelial MigrationR01HL077524 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI USHIO-FUKAI, MASUKO · 2006 to 2010
$2.2MEffects of Low Carbohydrate and Low Fat Diets on Endothelium Function in ObesityR01HL095701 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI PHILLIPS, SHANE A · 2010 to 2014
$2.1MMechanisms of myeloperoxidase and Nox4 interactions in abdominal aortic aneurysmR01HL142097 · NHLBI · AUGUSTA UNIVERSITY · PI WEINTRAUB, NEAL L · 2018 to 2021
$2.1MLipid macropinocytosis: a novel target in atherosclerotic cardiovascular diseaseR01HL139562 · NHLBI · AUGUSTA UNIVERSITY · PI CSANYI, GABOR · 2018 to 2022
$1.9MEpigenetic regulation of HDAC9 in obesity and atherosclerosisR01HL126949 · NHLBI · AUGUSTA UNIVERSITY · PI WEINTRAUB, NEAL L · 2016 to 2019
$1.8MAmerican Heart Association-American Stroke Association 17POST33660754BLRD VA I01 BX001232BLRD VA I01 BX002095NCI NIH HHS R01 CA212608NHLBI NIH HHS K23 HL085614NHLBI NIH HHS R01 HL070187NHLBI NIH HHS R01 HL077524NHLBI NIH HHS R01 HL095701NHLBI NIH HHS R01 HL116976NHLBI NIH HHS R01 HL126949NHLBI NIH HHS R01 HL130513NHLBI NIH HHS R01 HL133613NHLBI NIH HHS R01 HL134354NHLBI NIH HHS R01 HL135584NHLBI NIH HHS R01 HL139562NHLBI NIH HHS R01 HL142097NHLBI NIH HHS R01 HL147550NHLBI NIH HHS R21 HL112293
Abstract
objectiveCopper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide. We reported that ATP7A protein expression and SOD3 activity are decreased in insulin-deficient type 1 diabetes mellitus vessels, thereby, inducing superoxide-mediated endothelial dysfunction, which are rescued by insulin treatment. However, it is unknown regarding the mechanism by which insulin increases ATP7A expression in VSMCs and whether ATP7A downregulation is observed in T2DM (type2 diabetes mellitus) mice and human in which insulin-Akt (protein kinase B) pathway is selectively impaired. APPROACH AND
resultsHere we show that ATP7A protein is markedly downregulated in vessels isolated from T2DM patients, as well as those from high-fat diet-induced or db/db T2DM mice. Akt2 (protein kinase B beta) activated by insulin promotes ATP7A stabilization via preventing ubiquitination/degradation as well as translocation to plasma membrane in VSMCs, which contributes to activation of SOD3 that protects against T2DM-induced endothelial dysfunction. Downregulation of ATP7A in T2DM vessels is restored by constitutive active Akt or PTP1B
conclusionAkt2 plays a critical role in ATP7A protein stabilization and translocation to plasma membrane in VSMCs, which contributes to full activation of vascular SOD3 that protects against endothelial dysfunction in T2DM.
Indexed as
AnimalsAorta, ThoracicCells, CulturedCopper-Transporting ATPasesDiabetes Mellitus, ExperimentalDiabetes Mellitus, Type 2Diabetic AngiopathiesEndothelium, VascularEnzyme StabilityFemaleHumansHypoglycemic AgentsInsulinMaleMesenteric ArteriesMice, Inbred C57BLAkt1 protein, mouseAkt2 protein, mouseAtp7a protein, mouseCopper-Transporting ATPasesHypoglycemic AgentsInsulinProto-Oncogene Proteins c-aktSod3 protein, mouseSuperoxide DismutaseAkt2 proteincopper-transporting ATPaseendothelial dysfunctiontype 2 diabetes mellitusvascular smooth muscle
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