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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]
  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. https://doi.org/10.1161/ATVBAHA.119.313374.
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
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.
@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}
}

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