title: Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy.
abstract: BACKGROUND
  Sustained pressure overload induces pathological cardiac hypertrophy and dysfunction. Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction.
  
  
  RESULTS
  C57/Bl6 mice underwent transverse aortic constriction for 4 weeks, increasing cardiac mass (190%) and diastolic dimension (144%), lowering ejection fraction (-46%), and triggering NOS uncoupling and oxidative stress. Oral BH4 was then administered for 5 more weeks of pressure overload. Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothelial NOS, lowered oxidant stress, and improved chamber and myocyte function, whereas untreated hearts worsened. If BH4 was started at the onset of pressure overload, it did not suppress hypertrophy over the first week when NOS activity remained preserved even in untreated transverse aortic constriction hearts. However, BH4 stopped subsequent remodeling when NOS activity was otherwise declining. A broad antioxidant, Tempol, also reduced oxidant stress yet did not recouple NOS or reverse worsened hypertrophy/fibrosis from sustained transverse aortic constriction. Microarray analysis revealed very different gene expression profiles for both treatments. BH4 did not enhance net protein kinase G activity. Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprotected against pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts.
  
  
  CONCLUSIONS
  NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy/fibrosis and is more effective than a less targeted antioxidant approach (Tempol). These data highlight the importance of myocyte NOS uncoupling in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder.
authors.affiliation: Johns Hopkins Medical Institutions, Division of Cardiology, Baltimore, MD 21205, USA.
authors.forename: An L
authors.initials: AL
authors.lastname: Moens
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.forename: Khalid
authors.initials: K
authors.lastname: Chakir
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Cormaci
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ketner
authors.forename: Maulik
authors.initials: M
authors.lastname: Majmudar
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Alp
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006332:Cardiomegaly / Q000188:drug therapy*; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy*; D006136:GTP Cyclohydrolase / Q000235:genetics; D020869:Gene Expression Profiling; D006973:Hypertension / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D013113:Spin Labels
chemical_list: D003497:Cyclic N-Oxides; D013113:Spin Labels; D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase; C003402:sapropterin; C001803:tempol