title: NOX isoforms in the development of abdominal aortic aneurysm.
abstract: Oxidative stress plays an important role in the formation of abdominal aortic aneurysm (AAA), and we have recently established a causal role of uncoupled eNOS in this severe human disease. We have also shown that activation of NADPH oxidase (NOX) lies upstream of uncoupled eNOS. Therefore, identification of the specific NOX isoforms that are required for eNOS uncoupling and AAA formation would ultimately lead to novel therapies for AAA. In the present study, we used the Ang II infused hph-1 mice to examine the roles of NOX isoforms in the development of AAA. We generated double mutants of hph-1-NOX1, hph-1-NOX2, hph-1-p47phox, and hph-1-NOX4. After two weeks of Ang II infusion, the incidence rate of AAA substantially dropped from 76.5% in Ang II infused hph-1 mice (n=34) to 11.1%, 15.0%, 9.5% and 0% in hph-1-NOX1 (n=27), hph-1-NOX2 (n=40), hph-1-p47phox (n=21), and hph-1-NOX4 (n=33) double mutant mice, respectively. The size of abdominal aortas of the four double mutant mice, determined by ultrasound analyses, was significantly smaller than the hph-1 mice. Aortic nitric oxide and H4B bioavailabilities were markedly improved in the double mutants, while superoxide production and eNOS uncoupling activity were substantially diminished. These effects seemed attributed to an endothelial specific restoration of dihydrofolate reductase expression and activity, deficiency of which has been shown to induce eNOS uncoupling and AAA formation in both Ang II-infused hph-1 and apoE null animals. In addition, over-expression of human NOX4 N129S or T555S mutant newly identified in aneurysm patients increased hydrogen peroxide production, further implicating a relationship between NOX and human aneurysm. Taken together, these data indicate that NOX isoforms 1, 2 or 4 lies upstream of dihydrofolate reductase deficiency and eNOS uncoupling to induce AAA formation. These findings may promote development of novel therapeutics for the treatment of the disease by inhibiting NOX signaling.
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA 90095, USA.
authors.forename: Kin Lung
authors.initials: KL
authors.lastname: Siu
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA 90095, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA 90095, USA.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA 90095, USA.
authors.forename: Ji Youn
authors.initials: JY
authors.lastname: Youn
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, 650 Charles E. Young Drive, Los Angeles, CA 90095, USA. Electronic address: hcai@mednet.ucla.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009154:Mutation; D000074663:NADPH Oxidase 4 / Q000235:genetics*; D019255:NADPH Oxidases / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000172:deficiency / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C103827:Phc1 protein, mouse; D020033:Protein Isoforms; D013481:Superoxides; D000804:Angiotensin II; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D013762:Tetrahydrofolate Dehydrogenase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C060505:neutrophil cytosolic factor 1; D063150:Polycomb Repressive Complex 1
keywords: Abdominal aortic aneurysms (AAA); Angiotensin II (Ang II); Dihydrofolate reductase (DHFR); Endothelial nitric oxide synthase (eNOS) uncoupling; NOX1; NOX2; NOX4; Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase/NOX); Nitric oxide (NO); Superoxide; Tetrahydrobiopterin (H(4)B); p47phox