title: Intermedin1-53 Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress.
abstract: Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress.
  
  
  
  In angiotensin II-induced ApoE-/-mouse and CaCl2-induced C57BL/6J mouse model of AAA, IMD1-53significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff-van Gieson staining showed that IMD1-53significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl2. Mechanistically, IMD1-53attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD1-53inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAA mice. Expression of Nox4 was upregulated in human AAA segments and in angiotensin II-treated mouse aortas and was markedly decreased by IMD1-53. In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II-induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD17-47and protein kinase A inhibitor H89 inhibited the effect of IMD1-53, reducing Nox4 protein levels.
  
  
  
  IMD1-53could have a protective effect on AAA by inhibiting oxidative stress.
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Lu
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Jia
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Xian-Qiang
authors.initials: XQ
authors.lastname: Ni
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Jin-Rui
authors.initials: JR
authors.lastname: Chang
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Jin-Sheng
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Yue-Long
authors.initials: YL
authors.lastname: Hou
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: You-Fei
authors.initials: YF
authors.lastname: Guan
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Yan-Rong
authors.initials: YR
authors.lastname: Yu
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.).
authors.forename: Chao-Shu
authors.initials: CS
authors.lastname: Tang
authors.affiliation: From the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China (W.-W.L., L.-X.J., X.-Q.N., L.Z., Y.-L.H., J.D., Y.-F.Q.); Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., L.Z., J.-R.C., J.-S.Z., Y.Z., Y.-F.G., C.-S.T., Y.-F.Q.); and Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China (W.-W.L., X.-Q.N., J.-S.Z., Y.-L.H., Y.-R.Y., Y.-F.Q.). yongfenqi@163.com.
authors.forename: Yong-Fen
authors.initials: YF
authors.lastname: Qi
mesh_terms: D053607:Adrenomedullin / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D002122:Calcium Chloride; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: C484330:ADM2 protein, human; C499411:Adm2 protein, rat; D000975:Antioxidants; D001057:Apolipoproteins E; D009479:Neuropeptides; D036361:Peptide Hormones; C514552:intermedin protein, mouse; D000804:Angiotensin II; D053607:Adrenomedullin; D000242:Cyclic AMP; D019255:NADPH Oxidases; D017868:Cyclic AMP-Dependent Protein Kinases; D002122:Calcium Chloride
keywords: NAD(P)H oxidase; abdominal aortic aneurysm; angiotensin II; oxidative stress