Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia

Roman N. Rodionov, Hayan Dayoub, Cynthia M. Lynch, Katina M. Wilson, Jeff W. Stevens, Daryl J Murry, Masumi Kimoto, Erland Arning, Teodoro Bottiglieri, John P. Cooke, Gary L. Baumbach, Frank M. Faraci, Steven R. Lentz

Research output: Contribution to journalArticle

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Abstract

Rationale: Hyperhomocysteinemia is a cardiovascular risk factor that is associated with elevation of the nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA). Objective: Using mice transgenic for overexpression of the ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1), we tested the hypothesis that overexpression of DDAH1 protects from adverse structural and functional changes in cerebral arterioles in hyperhomocysteinemia. Methods And Results: Hyperhomocysteinemia was induced in DDAH1 transgenic (DDAH1 Tg) mice and wild-type littermates using a high methionine/low folate (HM/LF) diet. Plasma total homocysteine was elevated approximately 3-fold in both wild-type and DDAH1 Tg mice fed the HM/LF diet compared with the control diet (P<0.001). Plasma ADMA was approximately 40% lower in DDAH1 Tg mice compared with wild-type mice (P<0.001) irrespective of diet. Compared with the control diet, the HM/LF diet diminished endothelium-dependent dilation to 10 μmol/L acetylcholine in cerebral arterioles of both wild-type (12±2 versus 29±3%; P<0.001) and DDAH1 Tg (14±3 versus 28±2%; P<0.001) mice. Responses to 10 μmol/L papaverine, a direct smooth muscle dilator, were impaired with the HM/LF diet in wild-type mice (30±3 versus 45±5%; P<0.05) but not DDAH1 Tg mice (45±7 versus 48±6%). DDAH1 Tg mice also were protected from hypertrophy of cerebral arterioles (P<0.05) but not from accelerated carotid artery thrombosis induced by the HM/LF diet. Conclusions: Overexpression of DDAH1 protects from hyperhomocysteinemia-induced alterations in cerebral arteriolar structure and vascular muscle function.

Original languageEnglish (US)
Pages (from-to)551-558
Number of pages8
JournalCirculation Research
Volume106
Issue number3
DOIs
StatePublished - Feb 1 2010

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Hyperhomocysteinemia
Blood Vessels
Diet
Folic Acid
Methionine
Arterioles
Transgenic Mice
Carotid Artery Thrombosis
dimethylargininase
Papaverine
Homocysteine
Nitric Oxide Synthase
Hypertrophy
Acetylcholine
Endothelium
Smooth Muscle
Dilatation
Muscles

Keywords

  • Amino acids
  • Endothelium
  • Nitric oxide synthase
  • Thrombosis
  • Vasodilation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia. / Rodionov, Roman N.; Dayoub, Hayan; Lynch, Cynthia M.; Wilson, Katina M.; Stevens, Jeff W.; Murry, Daryl J; Kimoto, Masumi; Arning, Erland; Bottiglieri, Teodoro; Cooke, John P.; Baumbach, Gary L.; Faraci, Frank M.; Lentz, Steven R.

In: Circulation Research, Vol. 106, No. 3, 01.02.2010, p. 551-558.

Research output: Contribution to journalArticle

Rodionov, RN, Dayoub, H, Lynch, CM, Wilson, KM, Stevens, JW, Murry, DJ, Kimoto, M, Arning, E, Bottiglieri, T, Cooke, JP, Baumbach, GL, Faraci, FM & Lentz, SR 2010, 'Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia', Circulation Research, vol. 106, no. 3, pp. 551-558. https://doi.org/10.1161/CIRCRESAHA.109.200360
Rodionov, Roman N. ; Dayoub, Hayan ; Lynch, Cynthia M. ; Wilson, Katina M. ; Stevens, Jeff W. ; Murry, Daryl J ; Kimoto, Masumi ; Arning, Erland ; Bottiglieri, Teodoro ; Cooke, John P. ; Baumbach, Gary L. ; Faraci, Frank M. ; Lentz, Steven R. / Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia. In: Circulation Research. 2010 ; Vol. 106, No. 3. pp. 551-558.
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AU - Dayoub, Hayan

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AU - Wilson, Katina M.

AU - Stevens, Jeff W.

AU - Murry, Daryl J

AU - Kimoto, Masumi

AU - Arning, Erland

AU - Bottiglieri, Teodoro

AU - Cooke, John P.

AU - Baumbach, Gary L.

AU - Faraci, Frank M.

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