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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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.",
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AU - Dayoub, Hayan

AU - Lynch, Cynthia M.

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.

AU - Lentz, Steven R.

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N2 - 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.

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KW - Endothelium

KW - Nitric oxide synthase

KW - Thrombosis

KW - Vasodilation

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