title: Adrenomedullin gene delivery is cardio-protective in a model of chronic nitric oxide deficiency combining pressure overload, oxidative stress and cardiomyocyte hypertrophy.
abstract: OBJECTIVE
  Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of the vasodilator peptide, adrenomedullin (AM) and its receptors is augmented in cardiomyocytes, indicating that the myocardial AM system may be activated in response to pressure loading and ischemic insult to serve a counter-regulatory, cardio-protective role. The study examined the hypothesis that oxidative stress and hypertrophic remodeling in NO-deficient cardiomyocytes are attenuated by adenoviral vector-mediated delivery of the human adrenomedullin (hAM) gene in vivo.
  
  
  METHODS
  The NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 15mg . kg(-1) . day(-1)) was given to rats for 4 weeks following systemic administration via the tail vein of a single injection of either adenovirus harbouring hAM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM-4F2), or for comparison, adenovirus alone (Ad.Null) or saline. Cardiomyocytes were subsequently isolated for assessment of the influence of each intervention on parameters of oxidative stress and hypertrophic remodelling.
  
  
  RESULTS
  Cardiomyocyte expression of the transgene persisted for > or =4 weeks following systemic administration of adenoviral vector. In L-NAME treated rats, relative to Ad.Null or saline administration, Ad.CMV-hAM-4F2 (i) reduced augmented cardiomyocyte membrane protein oxidation and mRNA expression of pro-oxidant (p22phox) and anti-oxidant (SOD-3, GPx) genes; (ii) attenuated increased cardiomyocyte width and mRNA expression of hypertrophic (sk-alpha-actin) and cardio-endocrine (ANP) genes; (iii) did not attenuate hypertension.
  
  
  CONCLUSIONS
  Adenoviral vector mediated delivery of hAM resulted in attenuation of myocardial oxidative stress and hypertrophic remodelling in the absence of blood pressure reduction in this model of chronic NO-deficiency. These findings are consistent with a direct cardio-protective action in the myocardium of locally-derived hAM which is not dependant on NO generation.
authors.affiliation: School of Medicine, Dentistry and Biomedical Sciences, The Queen's University of Belfast, Belfast, Northern Ireland. d.bell@qub.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Bell
authors.forename: Malcolm
authors.initials: M
authors.lastname: Campbell
authors.forename: Xuanhui
authors.initials: X
authors.lastname: Wang
authors.forename: J A Philip
authors.initials: JA
authors.lastname: Earle
authors.forename: S Louise
authors.initials: SL
authors.lastname: Cosby
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: McDermott
mesh_terms: D053607:Adrenomedullin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000172:deficiency; D018384:Oxidative Stress; D011312:Pressure; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: C507862:ADM protein, human; D053607:Adrenomedullin; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; C499089:Sod3 protein, rat; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D019331:NG-Nitroarginine Methyl Ester