title: Polymerase delta interacting protein 2 sustains vascular structure and function.
abstract: OBJECTIVE
  On the basis of previous evidence that polymerase delta interacting protein 2 (Poldip2) increases reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) activity in vascular smooth muscle cells, we hypothesized that in vivo knockdown of Poldip2 would inhibit reactive oxygen species production and alter vascular function.
  
  
  RESULTS
  Because homozygous Poldip2 deletion is lethal, Poldip2(+/-) mice were used. Poldip2 mRNA and protein levels were reduced by ≈50% in Poldip2(+/-) aorta, with no change in p22phox, Nox1, Nox2, and Nox4 mRNAs. NADPH oxidase activity was also inhibited in Poldip2(+/-) tissue. Isolated aortas from Poldip2(+/-) mice demonstrated impaired phenylephrine and potassium chloride-induced contractions, increased stiffness, and reduced compliance associated with disruption of elastic lamellae and excessive extracellular matrix deposition. Collagen I secretion was elevated in cultured vascular smooth muscle cells from Poldip2(+/-) mice and restored by H2O2 supplementation, suggesting that this novel function of Poldip2 is mediated by reactive oxygen species. Furthermore, Poldip2(+/-) mice were protected against aortic dilatation in a model of experimental aneurysm, an effect consistent with increased collagen secretion.
  
  
  CONCLUSIONS
  Poldip2 knockdown reduces H2O2 production in vivo, leading to increases in extracellular matrix, greater vascular stiffness, and impaired agonist-mediated contraction. Thus, unaltered expression of Poldip2 is necessary for vascular integrity and function.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Atlanta Veterans Affairs Medical Center and Emory University School of Medicine, Decatur, GA, USA.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.forename: Lula L
authors.initials: LL
authors.lastname: Hilenski
authors.forename: Angélica M
authors.initials: AM
authors.lastname: Amanso
authors.forename: Ioannis
authors.initials: I
authors.lastname: Parastatidis
authors.forename: Anna E
authors.initials: AE
authors.lastname: Dikalova
authors.forename: Laura
authors.initials: L
authors.lastname: Hansen
authors.forename: Srinivasa Raju
authors.initials: SR
authors.lastname: Datla
authors.forename: James S
authors.initials: JS
authors.lastname: Long
authors.forename: Alexander M
authors.initials: AM
authors.lastname: El-Ali
authors.forename: Giji
authors.initials: G
authors.lastname: Joseph
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Gleason
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.forename: C Michael
authors.initials: CM
authors.lastname: Hart
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
authors.forename: Bernard
authors.initials: B
authors.lastname: Lassègue
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001014:Aortic Aneurysm / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004547:Elastic Tissue / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D059289:Vascular Stiffness; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation
chemical_list: D024042:Collagen Type I; D003573:Cytochrome b Group; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; C514737:mitogenin 1 protein, mouse; D009247:NADH, NADPH Oxidoreductases; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C422943:Nox4 protein, mouse; C515614:Cyba protein, mouse
keywords: Nox4; Poldip2; blood vessel; extracellular matrix; hydrogen peroxide