title: Nicotinamide Phosphoribosyltransferase in Smooth Muscle Cells Maintains Genome Integrity, Resists Aortic Medial Degeneration, and Is Suppressed in Human Thoracic Aortic Aneurysm Disease.
abstract: BACKGROUND
  The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage, but their capacities decline with age and stress. Recently, cellular production of nicotinamide adenine dinucleotide (NAD+) via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown.
  
  
  OBJECTIVE
  To determine whether a Nampt-NAD+control system exists within the aortic media and is required for aortic health.
  
  
  RESULTS
  Ascending aortas from patients with dilated aortopathy were immunostained for NAMPT, revealing an inverse relationship between SMC NAMPT content and aortic diameter. To determine whether a Nampt-NAD+control system in SMCs impacts aortic integrity, mice withNampt-deficient SMCs were generated. SMC-Namptknockout mice were viable but with mildly dilated aortas that had a 43% reduction in NAD+in the media. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs were not apoptotic but displayed senescence associated-ß-galactosidase activity and upregulated p16, indicating premature senescence. Furthermore, there was evidence for oxidized DNA lesions, double-strand DNA strand breaks, and pronounced susceptibility to single-strand breakage. This was linked to suppressed poly(ADP-ribose) polymerase-1 activity and was reversible on resupplying NAD+with nicotinamide riboside. Remarkably, we discovered unrepaired DNA strand breaks in SMCs within the human ascending aorta, which were specifically enriched in SMCs with low NAMPT.NAMPTpromoter analysis revealed CpG hypermethylation within the dilated human thoracic aorta and in SMCs cultured from these tissues, which inversely correlated withNAMPTexpression.
  
  
  CONCLUSIONS
  The aortic media depends on an intrinsic NAD+fueling system to protect against DNA damage and premature SMC senescence, with relevance to human thoracic aortopathy.
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Alanna
authors.initials: A
authors.lastname: Watson
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Zengxuan
authors.initials: Z
authors.lastname: Nong
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Caroline
authors.initials: C
authors.lastname: O'Neil
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fox
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Brittany
authors.initials: B
authors.lastname: Balint
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Linrui
authors.initials: L
authors.lastname: Guo
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Oberdan
authors.initials: O
authors.lastname: Leo
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Michael W A
authors.initials: MWA
authors.lastname: Chu
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.affiliation: From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.). gpickering@robarts.ca.
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D004249:DNA Damage / Q000502:physiology*; D005260:Female; D016678:Genome / Q000502:physiology*; D006801:Humans; D061346:Laser Capture Microdissection / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D017540:Tunica Media / Q000473:pathology / Q000502:physiology*
chemical_list: D016207:Cytokines; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C495867:nicotinamide phosphoribosyltransferase, mouse
keywords: DNA damage; aortic disease; cell aging; extracellular matrix