Reduction of NADPH-Oxidase Activity Ameliorates the Cardiovascular Phenotype in a Mouse Model of Williams-Beuren Syndrome

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A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS patients against hypertension, likely through reduced NADPH-oxidase (NOX)–mediated oxidative stress. DD mice, carrying a 0.67 Mb heterozygous deletion including the Eln gene, presented with a generalized arteriopathy, hypertension, and cardiac hypertrophy, associated with elevated angiotensin II (angII), oxidative stress parameters, and Ncf1 expression. Genetic (by crossing with Ncf1 mutant) and/or pharmacological (with ang II type 1 receptor blocker, losartan, or NOX inhibitor apocynin) reduction of NOX activity controlled hormonal and biochemical parameters in DD mice, resulting in normalized blood pressure and improved cardiovascular histology. We provide strong evidence for implication of the redox system in the pathophysiology of the cardiovascular disease in a mouse model of WBS. The phenotype of these mice can be ameliorated by either genetic or pharmacological intervention reducing NOX activity, likely through reduced angII–mediated oxidative stress. Therefore, anti-NOX therapy merits evaluation to prevent the potentially serious cardiovascular complications of WBS, as well as in other cardiovascular disorders mediated by similar pathogenic mechanism.

Vyšlo v časopise: Reduction of NADPH-Oxidase Activity Ameliorates the Cardiovascular Phenotype in a Mouse Model of Williams-Beuren Syndrome. PLoS Genet 8(2): e32767. doi:10.1371/journal.pgen.1002458
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002458

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1. PeoplesRFrankeYWangYKPerez-JuradoLPapernaT 2000 A physical map, including a BAC/PAC clone contig, of the Williams-Beuren syndrome–deletion region at 7q11.23. Am J Hum Genet 66 47 68

2. PoberBR 2010 Williams-Beuren syndrome. N Engl J Med 362 239 252

3. BayesMMaganoLFRiveraNFloresRPerez JuradoLA 2003 Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet 73 131 151

4. PoberBRJohnsonMUrbanZ 2008 Mechanisms and treatment of cardiovascular disease in Williams-Beuren syndrome. J Clin Invest 118 1606 1615

5. O'ConnorWNDavisJBJrGeisslerRCottrillCMNoonanJA 1985 Supravalvular aortic stenosis. Clinical and pathologic observations in six patients. Arch Pathol Lab Med 109 179 185

6. ReinAJPremingerTJPerrySBLockJESandersSP 1993 Generalized arteriopathy in Williams syndrome: an intravascular ultrasound study. J Am Coll Cardiol 21 1727 1730

7. TassabehjiMMetcalfeKDonnaiDHurstJReardonW 1997 Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. Hum Mol Genet 6 1029 1036

8. BroderKReinhardtEAhernJLiftonRTamborlaneW 1999 Elevated ambulatory blood pressure in 20 subjects with Williams syndrome. Am J Med Genet 83 356 360

9. WesselAGravenhorstVBuchhornRGoschAPartschCJ 2004 Risk of sudden death in the Williams-Beuren syndrome. Am J Med Genet A 127A 234 237

10. DietzHCMechamRP 2000 Mouse models of genetic diseases resulting from mutations in elastic fiber proteins. Matrix Biol 19 481 488

11. GoergenCJLiHHFranckeUTaylorCA 2011 Induced chromosome deletion in a Williams-Beuren syndrome mouse model causes cardiovascular abnormalities. J Vasc Res 48 119 129

12. LiDYFauryGTaylorDGDavisECBoyleWA 1998 Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest 102 1783 1787

13. FauryGPezetMKnutsenRHBoyleWAHeximerSP 2003 Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest 112 1419 1428

14. LeeMYGriendlingKK 2008 Redox signaling, vascular function, and hypertension. Antioxid Redox Signal 10 1045 1059

15. Del CampoMAntonellAMaganoLFMunozFJFloresR 2006 Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension. Am J Hum Genet 78 533 542

16. LandmesserUSpiekermannSDikalovSTatgeHWilkeR 2002 Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 106 3073 3078

17. LiHHRoyMKuscuogluUSpencerCMHalmB 2009 Induced chromosome deletions cause hypersociability and other features of Williams-Beuren syndrome in mice. EMBO Mol Med 1 50 65

18. HultqvistMOlofssonPHolmbergJBackstromBTTordssonJ 2004 Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc Natl Acad Sci U S A 101 12646 12651

19. AlwanSPolifkaJEFriedmanJM 2005 Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol 73 123 130

20. QuanA 2006 Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Early Hum Dev 82 23 28

21. BirdLMBillmanGFLacroRVSpicerRLJariwalaLK 1996 Sudden death in Williams syndrome: report of ten cases. J Pediatr 129 926 931

22. EronenMPeippoMHiippalaARaatikkaMArvioM 2002 Cardiovascular manifestations in 75 patients with Williams syndrome. J Med Genet 39 554 558

23. GiordanoUTurchettaAGiannottiADigilioMCVirgiliiF 2001 Exercise testing and 24-hour ambulatory blood pressure monitoring in children with Williams syndrome. Pediatr Cardiol 22 509 511

24. RoseCWesselAPankauRPartschCJBurschJ 2001 Anomalies of the abdominal aorta in Williams-Beuren syndrome–another cause of arterial hypertension. Eur J Pediatr 160 655 658

25. WollackJBKaiferMLaMonteMPRothmanM 1996 Stroke in Williams syndrome. Stroke 27 143 146

26. CherniskeEMCarpenterTOKlaimanCYoungEBregmanJ 2004 Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A 131 255 264

27. WesselAMotzRPankauRBurschJH 1997 [Arterial hypertension and blood pressure profile in patients with Williams-Beuren syndrome]. Z Kardiol 86 251 257

28. TsoporisJKeeleyFWLeeRMLeenenFH 1998 Arterial vasodilation and vascular connective tissue changes in spontaneously hypertensive rats. J Cardiovasc Pharmacol 31 960 962

29. PierceRAMariencheckWISandefurSCrouchECParksWC 1995 Glucocorticoids upregulate tropoelastin expression during late stages of fetal lung development. Am J Physiol 268 L491 500

30. McGowanSEDoroMMJacksonSK 1997 Endogenous retinoids increase perinatal elastin gene expression in rat lung fibroblasts and fetal explants. Am J Physiol 273 L410 416

31. SowersJR 2002 Hypertension, angiotensin II, and oxidative stress. N Engl J Med 346 1999 2001

32. ChabrashviliTTojoAOnozatoMLKitiyakaraCQuinnMT 2002 Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. Hypertension 39 269 274

33. CuscoICorominasRBayesMFloresRRivera-BruguesN 2008 Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion. Genome Res 18 683 694

34. KleinschnitzCGrundHWinglerKArmitageMEJonesE 2010 Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol 8 e1000479 doi:10.1371/journal.pbio.1000479

35. ParaviciniTMTouyzRM 2006 Redox signaling in hypertension. Cardiovasc Res 71 247 258

36. HabashiJPJudgeDPHolmTMCohnRDLoeysBL 2006 Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312 117 121

37. DrummondGRSelemidisSGriendlingKKSobeyCG 2011 Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 10 453 471

38. AdamsGNLaruschGAStavrouEZhouYNiemanMT 2011 Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis. Blood

39. StefanskaJSokolowskaMSarniakAWlodarczykADoniecZ 2010 Apocynin decreases hydrogen peroxide and nitrate concentrations in exhaled breath in healthy subjects. Pulm Pharmacol Ther 23 48 54

40. WindSBeuerleinKEuckerTMullerHScheurerP 2010 Comparative pharmacology of chemically distinct NADPH oxidase inhibitors. Br J Pharmacol 161 885 898

41. TangXNCairnsBCairnsNYenariMA 2008 Apocynin improves outcome in experimental stroke with a narrow dose range. Neuroscience 154 556 562

42. LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25 402 408

43. LauYEGalliganJJKreulenDLFinkGD 2006 Activation of ETB receptors increases superoxide levels in sympathetic ganglia in vivo. Am J Physiol Regul Integr Comp Physiol 290 R90 95