Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis

Johannes Jacobi, Karsten Sydow, Georges Von Degenfeld, Ying Zhang, Hayan Dayoub, Bingyin Wang, Andrew J. Patterson, Masumi Kimoto, Helen M. Blau, John P. Cooke

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Background - This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Methods and Results - In DDAH1 transgenic (TG) and wild-type mice (each n=42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each n=21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or Nω-nitro-L-arginine methyl ester (L-NAME; each 250 μmol·kg-1·d -1) by use of osmotic minipumps (each n=7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity. Conclusions - We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion.

Original languageEnglish (US)
Pages (from-to)1431-1438
Number of pages8
JournalCirculation
Volume111
Issue number11
DOIs
StatePublished - Mar 22 2005

Fingerprint

Nitric Oxide Synthase
Transgenic Mice
NG-Nitroarginine Methyl Ester
Hindlimb
Ischemia
Perfusion
Genetically Modified Animals
Enzymes
Microspheres
Extremities
N,N-dimethylarginine
dimethylargininase
Therapeutics

Keywords

  • Aminohydrolases
  • Angiogenesis
  • Arginine
  • Ischemia
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. / Jacobi, Johannes; Sydow, Karsten; Von Degenfeld, Georges; Zhang, Ying; Dayoub, Hayan; Wang, Bingyin; Patterson, Andrew J.; Kimoto, Masumi; Blau, Helen M.; Cooke, John P.

In: Circulation, Vol. 111, No. 11, 22.03.2005, p. 1431-1438.

Research output: Contribution to journalArticle

Jacobi, J, Sydow, K, Von Degenfeld, G, Zhang, Y, Dayoub, H, Wang, B, Patterson, AJ, Kimoto, M, Blau, HM & Cooke, JP 2005, 'Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis', Circulation, vol. 111, no. 11, pp. 1431-1438. https://doi.org/10.1161/01.CIR.0000158487.80483.09
Jacobi, Johannes ; Sydow, Karsten ; Von Degenfeld, Georges ; Zhang, Ying ; Dayoub, Hayan ; Wang, Bingyin ; Patterson, Andrew J. ; Kimoto, Masumi ; Blau, Helen M. ; Cooke, John P. / Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. In: Circulation. 2005 ; Vol. 111, No. 11. pp. 1431-1438.
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AU - Sydow, Karsten

AU - Von Degenfeld, Georges

AU - Zhang, Ying

AU - Dayoub, Hayan

AU - Wang, Bingyin

AU - Patterson, Andrew J.

AU - Kimoto, Masumi

AU - Blau, Helen M.

AU - Cooke, John P.

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N2 - Background - This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Methods and Results - In DDAH1 transgenic (TG) and wild-type mice (each n=42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each n=21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or Nω-nitro-L-arginine methyl ester (L-NAME; each 250 μmol·kg-1·d -1) by use of osmotic minipumps (each n=7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity. Conclusions - We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion.

AB - Background - This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Methods and Results - In DDAH1 transgenic (TG) and wild-type mice (each n=42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each n=21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or Nω-nitro-L-arginine methyl ester (L-NAME; each 250 μmol·kg-1·d -1) by use of osmotic minipumps (each n=7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity. Conclusions - We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion.

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