Varadarajan Sudhahar1,2,3, Archita Das1,2, Tetsuo Horimatsu1,4, Dipankar Ash1,4, Silvia Leanhart1,3, Olga Antipova5, Stefan Vogt5, Bhupesh Singla1,2, Gabor Csanyi1,2, Joseph White6, Jack H Kaplan7, David Fulton1,2, Neal L Weintraub1,4, Ha Won Kim1,4, Masuko Ushio-Fukai1,4, Tohru Fukai1,2,3. 1. From the Vascular Biology Center (V.S., A.D., T.H., D.A., S.L., B.S., G.C., D.F., N.L.W., H.W.K., M.U.-F., T.F.), Medical College of Georgia at Augusta University, GA. 2. Department of Pharmacology and Toxicology (V.S., A.D., B.S., G.C., D.F., T.F.), Medical College of Georgia at Augusta University, GA. 3. Charlie Norwood Veterans Affairs Medical Center, Augusta, GA (V.S., S.L., T.F.). 4. Department of Medicine (Cardiology) (T.H., D.A., N.L.W., H.W.K., M.U.-F.), Medical College of Georgia at Augusta University, GA. 5. X-ray Science Division, Argonne National Laboratory, IL (O.A., S.V.). 6. Department of Pathology (J.W.), Medical College of Georgia at Augusta University, GA. 7. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago (J.H.K.).
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, 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.
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, 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.
Authors: Sang-Woo Kim; Kumaraguruparan Ramasamy; Hakim Bouamar; An-Ping Lin; Daifeng Jiang; Ricardo C T Aguiar Journal: Proc Natl Acad Sci U S A Date: 2012-05-01 Impact factor: 11.205
Authors: Quintin Pan; Celina G Kleer; Kenneth L van Golen; Jennifer Irani; Kristen M Bottema; Carlos Bias; Magda De Carvalho; Enrique A Mesri; Diane M Robins; Robert D Dick; George J Brewer; Sofia D Merajver Journal: Cancer Res Date: 2002-09-01 Impact factor: 12.701
Authors: Lisa A Cassis; Manisha Gupte; Sarah Thayer; Xuan Zhang; Richard Charnigo; Deborah A Howatt; Debra L Rateri; Alan Daugherty Journal: Am J Physiol Heart Circ Physiol Date: 2009-02-27 Impact factor: 4.733
Authors: Varadarajan Sudhahar; Norifumi Urao; Jin Oshikawa; Ronald D McKinney; Roxana M Llanos; Julian F B Mercer; Masuko Ushio-Fukai; Tohru Fukai Journal: Diabetes Date: 2013-07-24 Impact factor: 9.461
Authors: Grzegorz Józef Nowicki; Barbara Ślusarska; Andrzej Prystupa; Eliza Blicharska; Agnieszka Adamczuk; Tomasz Czernecki; Krzysztof Jacek Jankowski Journal: Cardiol Res Pract Date: 2021-01-31 Impact factor: 1.866
Authors: Varadarajan Sudhahar; Mustafa Nazir Okur; John P O'Bryan; Richard D Minshall; David Fulton; Masuko Ushio-Fukai; Tohru Fukai Journal: Am J Physiol Cell Physiol Date: 2020-09-16 Impact factor: 4.249