title: The Paraoxonase Gene Cluster Protects Against Abdominal Aortic Aneurysm Formation.
abstract: OBJECTIVE
  Abdominal aortic aneurysm (AAA) is a life-threatening vascular pathology, the pathogenesis of which is closely related to oxidative stress. However, an effective pharmaceutical treatment is lacking because the exact cause of AAA remains unknown. Here, we aimed at delineating the role of the paraoxonases (PONs) gene cluster (PC), which prevents atherosclerosis through the detoxification of oxidized substrates, in AAA formation.
  
  
  RESULTS
  PC transgenic (Tg) mice were crossed to an Apoe-/-background, and an angiotensin II-induced AAA mouse model was used to analyze the effect of the PC on AAA formation. Four weeks after angiotensin II infusion, PC-Tg Apoe-/-mice had a lower AAA incidence, smaller maximal abdominal aortic external diameter, and less medial elastin degradation than Apoe-/-mice. Importantly, PC-Tg Apoe-/-mice exhibited lower aortic reactive oxidative species production and oxidative stress than did the Apoe-/-control mice. As a consequence, the PC transgene alleviated angiotensin II-induced arterial inflammation and suppressed arterial extracellular matrix degradation. Specifically, on angiotensin II stimulation, PC-Tg vascular smooth muscle cells exhibited lower levels of reactive oxidative species production and a decrease in the activities and expression levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. Moreover, PC-Tg serum also enhanced vascular smooth muscle cell oxidative stress resistance and further decreased the expression levels of matrix metalloproteinase-2 and matrix metalloproteinase-9, indicating that circulatory and vascular smooth muscle cell PC members suppress oxidative stress in a synergistic manner.
  
  
  CONCLUSIONS
  Our findings reveal, for the first time, a protective role of the PC in AAA formation and suggest PONs as promising targets for AAA prevention.
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yan
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Jian-Fei
authors.initials: JF
authors.lastname: Pei
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Zhu-Qin
authors.initials: ZQ
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.).
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China (Y.-F.Y., J.-F.P., Y.Z., R.Z., F.W., P.G., Z.-Q.Z., T.-T.W., Z.-G.S., H.-Z.C, D.-P.L.); and Key Laboratory of Tumor Molecular Biology, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, P.R. China (Y.-F.Y.). liudp@pumc.edu.cn chenhouzao@ibms.cams.cn.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D005810:Multigene Family; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D004549:Elastin; D043303:Aryldialkylphosphatase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: abdominal aortic aneurysm; angiotensin II; anti-oxidative stress; paraoxonase