Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b

Abstract

Objective: Copper (Cu) is essential micronutrient, and its dysregulation is implicated in aortic aneurysm (AA) development. The Cu exporter ATP7A (copper-transporting P-type ATPase/Menkes ATPase) delivers Cu via the Cu chaperone Atox1 (antioxidant 1) to secretory Cu enzymes, such as lysyl oxidase, and excludes excess Cu. Lysyl oxidase is shown to protect against AA formation. However, the role and mechanism of ATP7A in AA pathogenesis remain unknown. Approach and Results: Here, in this work, we show that Cu chelator markedly inhibited Ang II (angiotensin II)–induced abdominal AA (AAA) in which ATP7A expression was markedly downregulated. Transgenic ATP7A overexpression prevented Ang II–induced AAA formation. Conversely, Cu transport dysfunctional ATP7Amut/+/ApoE–/– mice exhibited robust AAA formation and dissection, excess aortic Cu accumulation as assessed by X-ray fluorescence microscopy, and reduced lysyl oxidase activity. In contrast, AAA formation was not observed in Atox1–/–/ApoE–/– mice, suggesting that decreased lysyl oxidase activity, which depends on both ATP7A and Atox1, was not sufficient to develop AAA. Bone marrow transplantation suggested importance of ATP7A in vascular cells, not bone marrow cells, in AAA development. MicroRNA (miR) array identified miR-125b as a highly upregulated miR in AAA from ATP7Amut/+/ApoE–/– mice. Furthermore, miR-125b target genes (histone methyltransferase Suv39h1 and the NF-κBmore » negative regulator TNFAIP3 [tumor necrosis factor alpha induced protein 3]) were downregulated, which resulted in increased proinflammatory cytokine expression, aortic macrophage recruitment, MMP (matrix metalloproteinase)-2/9 activity, elastin fragmentation, and vascular smooth muscle cell loss in ATP7Amut/+/ApoE–/– mice and reversed by locked nucleic acid-anti-miR-125b infusion. Conclusions: ATP7A downregulation/dysfunction promotes AAA formation via upregulating miR-125b, which augments proinflammatory signaling in a Cu-dependent manner. Thus, ATP7A is a potential therapeutic target for inflammatory vascular disease.« less

Authors:
 [1];  [2];  [2];  [2];  [1];  [3];  [3];  [2];  [2];  [2];  [4];  [2];  [2];  [2];  [2];  [1]
+ Show Author Affiliations
  1. Medical College of Georgia at Augusta Univ., GA (United States); Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (United States)
  2. Medical College of Georgia at Augusta Univ., GA (United States)
  3. Argonne National Lab. (ANL), Argonne, IL (United States)
  4. Univ. of Illinois, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); US Department of Veterans Affairs; USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1601448
Grant/Contract Number:  
AC02-06CH11357; NIHR01HL070187; 2I01BX001232; NIHR01HL133613; NIHR01HL116976; NIHR01 HL135584; 15SDG25700406; HL124097; HL126949; HL134354; AR070029; 17POST33660754
Resource Type:
Accepted Manuscript
Journal Name:
Arteriosclerosis, Thrombosis, and Vascular Biology
Additional Journal Information:
Journal Volume: 39; Journal Issue: 11; Journal ID: ISSN 1079-5642
Publisher:
American Heart Association
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; angiotensin II; aortic aneurysm; copper; elastin; micronutrient

Citation Formats

Sudhahar, Varadarajan, Das, Archita, Horimatsu, Tetsuo, Ash, Dipankar, Leanhart, Silvia, Antipova, Olga, Vogt, Stefan, Singla, Bhupesh, Csanyi, Gabor, White, Joseph, Kaplan, Jack H., Fulton, David, Weintraub, Neal L., Kim, Ha Won, Ushio-Fukai, Masuko, and Fukai, Tohru. Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b. United States: N. p., 2019. Web. doi:10.1161/ATVBAHA.119.313374.
Copy to clipboard
Sudhahar, Varadarajan, Das, Archita, Horimatsu, Tetsuo, Ash, Dipankar, Leanhart, Silvia, Antipova, Olga, Vogt, Stefan, Singla, Bhupesh, Csanyi, Gabor, White, Joseph, Kaplan, Jack H., Fulton, David, Weintraub, Neal L., Kim, Ha Won, Ushio-Fukai, Masuko, & Fukai, Tohru. Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b. United States. https://doi.org/10.1161/ATVBAHA.119.313374
Copy to clipboard
Sudhahar, Varadarajan, Das, Archita, Horimatsu, Tetsuo, Ash, Dipankar, Leanhart, Silvia, Antipova, Olga, Vogt, Stefan, Singla, Bhupesh, Csanyi, Gabor, White, Joseph, Kaplan, Jack H., Fulton, David, Weintraub, Neal L., Kim, Ha Won, Ushio-Fukai, Masuko, and Fukai, Tohru. Thu . "Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b". United States. https://doi.org/10.1161/ATVBAHA.119.313374. https://www.osti.gov/servlets/purl/1601448.
Copy to clipboard
@article{osti_1601448,
title = {Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b},
author = {Sudhahar, Varadarajan and Das, Archita and Horimatsu, Tetsuo and Ash, Dipankar and Leanhart, Silvia and Antipova, Olga and Vogt, Stefan and Singla, Bhupesh and Csanyi, Gabor and White, Joseph and Kaplan, Jack H. and Fulton, David and Weintraub, Neal L. and Kim, Ha Won and Ushio-Fukai, Masuko and Fukai, Tohru},
abstractNote = {Objective: Copper (Cu) is essential micronutrient, and its dysregulation is implicated in aortic aneurysm (AA) development. The Cu exporter ATP7A (copper-transporting P-type ATPase/Menkes ATPase) delivers Cu via the Cu chaperone Atox1 (antioxidant 1) to secretory Cu enzymes, such as lysyl oxidase, and excludes excess Cu. Lysyl oxidase is shown to protect against AA formation. However, the role and mechanism of ATP7A in AA pathogenesis remain unknown. Approach and Results: Here, in this work, we show that Cu chelator markedly inhibited Ang II (angiotensin II)–induced abdominal AA (AAA) in which ATP7A expression was markedly downregulated. Transgenic ATP7A overexpression prevented Ang II–induced AAA formation. Conversely, Cu transport dysfunctional ATP7Amut/+/ApoE–/– mice exhibited robust AAA formation and dissection, excess aortic Cu accumulation as assessed by X-ray fluorescence microscopy, and reduced lysyl oxidase activity. In contrast, AAA formation was not observed in Atox1–/–/ApoE–/– mice, suggesting that decreased lysyl oxidase activity, which depends on both ATP7A and Atox1, was not sufficient to develop AAA. Bone marrow transplantation suggested importance of ATP7A in vascular cells, not bone marrow cells, in AAA development. MicroRNA (miR) array identified miR-125b as a highly upregulated miR in AAA from ATP7Amut/+/ApoE–/– mice. Furthermore, miR-125b target genes (histone methyltransferase Suv39h1 and the NF-κB negative regulator TNFAIP3 [tumor necrosis factor alpha induced protein 3]) were downregulated, which resulted in increased proinflammatory cytokine expression, aortic macrophage recruitment, MMP (matrix metalloproteinase)-2/9 activity, elastin fragmentation, and vascular smooth muscle cell loss in ATP7Amut/+/ApoE–/– mice and reversed by locked nucleic acid-anti-miR-125b infusion. Conclusions: ATP7A downregulation/dysfunction promotes AAA formation via upregulating miR-125b, which augments proinflammatory signaling in a Cu-dependent manner. Thus, ATP7A is a potential therapeutic target for inflammatory vascular disease.},
doi = {10.1161/ATVBAHA.119.313374},
journal = {Arteriosclerosis, Thrombosis, and Vascular Biology},
number = 11,
volume = 39,
place = {United States},
year = {2019},
month = {9}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1161/ATVBAHA.119.313374
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 1 work
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Function and Regulation of Human Copper-Transporting ATPases
journal, July 2007

IGF-II is regulated by microRNA-125b in skeletal myogenesis
journal, January 2011

  • Ge, Yejing; Sun, Yuting; Chen, Jie
  • The Journal of Cell Biology, Vol. 192, Issue 1
  • DOI: 10.1083/jcb.201007165

Participation of ATP7A in macrophage mediated oxidation of LDL
journal, November 2009

  • Qin, Zhenyu; Konaniah, Eddy S.; Neltner, Bonnie
  • Journal of Lipid Research, Vol. 51, Issue 6
  • DOI: 10.1194/jlr.M003426

Orchidectomy, But Not Ovariectomy, Regulates Angiotensin II-Induced Vascular Diseases in Apolipoprotein E-Deficient Mice
journal, August 2004

  • Henriques, Tracy A.; Huang, Jing; D’Souza, Susan S.
  • Endocrinology, Vol. 145, Issue 8
  • DOI: 10.1210/en.2003-1615

Pathogenesis of Abdominal Aortic Aneurysms: MicroRNAs, Proteases, Genetic Associations
journal, January 2014

Deletion of p47 phox Attenuates Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E–Deficient Mice
journal, August 2006

Copper chelation by tetrathiomolybdate inhibits lipopolysaccharide-induced inflammatory responses in vivo
journal, September 2011

  • Wei, Hao; Frei, Balz; Beckman, Joseph S.
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 301, Issue 3
  • DOI: 10.1152/ajpheart.01299.2010

Alteration of copper physiology in mice overexpressing the human Menkes protein ATP7A
journal, May 2006

  • Ke, Bi-Xia; Llanos, Roxana M.; Wright, Magali
  • American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 290, Issue 5
  • DOI: 10.1152/ajpregu.00806.2005

Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo
journal, September 2016

  • Das, Archita; Sudhahar, Varadarajan; Chen, Gin-Fu
  • Scientific Reports, Vol. 6, Issue 1
  • DOI: 10.1038/srep33783

Direct Detection and Quantification of Transition Metal Ions in Human Atherosclerotic Plaques: Evidence for the Presence of Elevated Levels of Iron and Copper
journal, May 2004

Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function
journal, October 2015

  • Chen, Gin-Fu; Sudhahar, Varadarajan; Youn, Seock-Won
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep14780

Copper transporters and copper chaperones: roles in cardiovascular physiology and disease
journal, August 2018

  • Fukai, Tohru; Ushio-Fukai, Masuko; Kaplan, Jack H.
  • American Journal of Physiology-Cell Physiology, Vol. 315, Issue 2
  • DOI: 10.1152/ajpcell.00132.2018

Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms
journal, September 2002

  • Longo, G. Matthew; Xiong, Wanfen; Greiner, Timothy C.
  • Journal of Clinical Investigation, Vol. 110, Issue 5
  • DOI: 10.1172/JCI0215334

Thoracic and Abdominal Aortic Aneurysms
journal, February 2005

IL-1α, IL-1β and TNF-α secretion during in vivo/ex vivo cellular interactions with titanium and copper
journal, February 2003

Inflammatory Cell Phenotypes in AAAs: Their Role and Potential as Targets for Therapy
journal, August 2015

  • Dale, Matthew A.; Ruhlman, Melissa K.; Baxter, B. Timothy
  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 35, Issue 8
  • DOI: 10.1161/atvbaha.115.305269

Conditional Knockout of the Menkes Disease Copper Transporter Demonstrates Its Critical Role in Embryogenesis
journal, August 2012

Mechanisms for copper acquisition, distribution and regulation
journal, February 2008

  • Kim, Byung-Eun; Nevitt, Tracy; Thiele, Dennis J.
  • Nature Chemical Biology, Vol. 4, Issue 3
  • DOI: 10.1038/nchembio.72

The role of lysyl oxidase family members in the stabilization of abdominal aortic aneurysms
journal, October 2012

  • Remus, Ebony Washington; O'Donnell, Robert E.; Rafferty, Kathryn
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 303, Issue 8
  • DOI: 10.1152/ajpheart.00217.2012

Vascular complications (splenic and hepatic artery aneurysms) in the occipital horn syndrome: report of a patient and review of the literature
journal, January 1999

  • Mentzel, Hans-Joachim; Seidel, J�rg; Vogt, Susanna
  • Pediatric Radiology, Vol. 29, Issue 1
  • DOI: 10.1007/s002470050526

Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice
journal, April 2010

  • Yamanouchi, Dai; Morgan, Stephanie; Kato, Kaori
  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 30, Issue 4
  • DOI: 10.1161/atvbaha.109.200527

Pathophysiology and epidemiology of abdominal aortic aneurysms
journal, November 2010

  • Nordon, Ian M.; Hinchliffe, Robert J.; Loftus, Ian M.
  • Nature Reviews Cardiology, Vol. 8, Issue 2
  • DOI: 10.1038/nrcardio.2010.180

How Mammalian Cells Acquire Copper: An Essential but Potentially Toxic Metal
journal, January 2016

Understanding Abdominal Aortic Aneurysm
journal, September 2009

Female Mice With an XY Sex Chromosome Complement Develop Severe Angiotensin II–Induced Abdominal Aortic Aneurysms
journal, January 2017

Role of Menkes ATPase in Angiotensin II-Induced Hypertension: A Key Modulator for Extracellular Superoxide Dismutase Function
journal, November 2008

Role of myeloperoxidase in abdominal aortic aneurysm formation: mitigation by taurine
journal, December 2017

  • Kim, Ha Won; Blomkalns, Andra L.; Ogbi, Mourad
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 313, Issue 6
  • DOI: 10.1152/ajpheart.00296.2017

Copper chelation represses the vascular response to injury
journal, May 2003

  • Mandinov, L.; Mandinova, A.; Kyurkchiev, S.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 11
  • DOI: 10.1073/pnas.1231994100

Identification and characterization of microRNAs in vascular smooth muscle cells from patients with abdominal aortic aneurysms
journal, January 2014

  • Cheuk, Bernice Lai Yee; Cheng, Stephen Wing Keung
  • Journal of Vascular Surgery, Vol. 59, Issue 1
  • DOI: 10.1016/j.jvs.2013.02.244

MicroRNAs miR-125a and miR-125b constitutively activate the NF- B pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20)
journal, May 2012

  • Kim, S. -W.; Ramasamy, K.; Bouamar, H.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 20
  • DOI: 10.1073/pnas.1200081109

Lumbar and iliac artery aneurysms in Menkes’ disease: endovascular cover stent treatment of the lumbar artery aneurysm
journal, May 2005

Leukocyte–endothelial adhesion is impaired in the cremaster muscle microcirculation of the copper-deficient rat
journal, March 2001

MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R
journal, July 2012

Inactivation of the Lysyl Oxidase Gene Lox Leads to Aortic Aneurysms, Cardiovascular Dysfunction, and Perinatal Death in Mice
journal, November 2002

Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase
journal, January 2003

  • Hamza, I.; Prohaska, J.; Gitlin, J. D.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 3
  • DOI: 10.1073/pnas.0336230100

Lysyl oxidase: an oxidative enzyme and effector of cell function
journal, August 2006

Abdominal Aortic Aneurysm or Aortic Occlusive Disease: Role of Trace Element Imbalance
journal, April 2007

Micro-RNAs in abdominal aortic aneurysms: insights from animal models and relevance to human disease
journal, March 2016

  • Raffort, Juliette; Lareyre, Fabien; Clement, Marc
  • Cardiovascular Research, Vol. 110, Issue 2
  • DOI: 10.1093/cvr/cvw046

Abdominal aortic aneurysms: fresh insights from a novel animal model of the disease
journal, February 2002

Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function
journal, September 2012

  • Yoshioka, Kazuaki; Yoshida, Kotaro; Cui, Hong
  • Nature Medicine, Vol. 18, Issue 10
  • DOI: 10.1038/nm.2928

Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II–induced aortic aneurysms
journal, May 2009

  • Satoh, Kimio; Nigro, Patrizia; Matoba, Tetsuya
  • Nature Medicine, Vol. 15, Issue 6
  • DOI: 10.1038/nm.1958

Influence of metals on IL-6 release in vitro
journal, September 1998

ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice
journal, May 2009

  • Cassis, Lisa A.; Gupte, Manisha; Thayer, Sarah
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 296, Issue 5
  • DOI: 10.1152/ajpheart.00028.2009

An Overview of Matrix Metalloproteinases in the Pathogenesis and Treatment of Abdominal Aortic Aneurysms
journal, November 2005

  • Keeling, W. Brent; Armstrong, Paul A.; Stone, Patrick A.
  • Vascular and Endovascular Surgery, Vol. 39, Issue 6
  • DOI: 10.1177/153857440503900601

Copper-Induced Deregulation of microRNA Expression in the Zebrafish Olfactory System
journal, June 2013

  • Wang, Lu; Bammler, Theo K.; Beyer, Richard P.
  • Environmental Science & Technology, Vol. 47, Issue 13
  • DOI: 10.1021/es400615q

ATP7A-related copper transport diseases—emerging concepts and future trends
journal, January 2011

Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E–deficient mice
journal, June 2000

  • Daugherty, Alan; Manning, Michael W.; Cassis, Lisa A.
  • Journal of Clinical Investigation, Vol. 105, Issue 11
  • DOI: 10.1172/JCI7818

The molecular basis of copper-transport diseases
journal, February 2001

Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases
journal, September 2011

  • Fukai, Tohru; Ushio-Fukai, Masuko
  • Antioxidants & Redox Signaling, Vol. 15, Issue 6
  • DOI: 10.1089/ars.2011.3999

Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans
journal, July 2016

  • Lee, Vivian S.; Halabi, Carmen M.; Hoffman, Erin P.
  • Proceedings of the National Academy of Sciences, Vol. 113, Issue 31
  • DOI: 10.1073/pnas.1601442113

Mouse Models of Abdominal Aortic Aneurysms
journal, March 2004

Anticopper therapy against cancer and diseases of inflammation and fibrosis
journal, August 2005

Age of onset, pattern of distribution, and histology of aneurysm development in a genetically predisposed mouse model
journal, July 1988

Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation
journal, January 2003

    Sort by:
    [ × clear filter / sort ]

    Similar Records in DOE PAGES and OSTI.GOV collections: