Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia.

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 micromol/L acetylcholine in cerebral arterioles of both wild-type (12 + or - 2 versus 29 + or - 3%; P<0.001) and DDAH1 Tg (14 + or - 3 versus 28 + or - 2%; P<0.001) mice. Responses to 10 micromol/L papaverine, a direct smooth muscle dilator, were impaired with the HM/LF diet in wild-type mice (30 + or - 3 versus 45 + or - 5%; P<0.05) but not DDAH1 Tg mice (45 + or - 7 versus 48 + or - 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.

• Authors: 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
• Journal: Circulation research (Circ Res) Vol. 106 Issue 3 Pg. 551-8 (Feb 19 2010) ISSN: 1524-4571 [Electronic] United States
• PMID: 20019334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Vasodilator Agents
• N,N-dimethylarginine
• Arginine
• Methionine
• Papaverine
• Amidohydrolases
• dimethylargininase
• Acetylcholine

Topics

• Acetylcholine (pharmacology)
• Amidohydrolases (genetics, physiology)
• Animals
• Arginine (analogs & derivatives, blood)
• Arterioles (pathology)
• Carotid Artery Thrombosis (etiology)
• Cerebral Arterial Diseases (etiology, prevention & control)
• Diet (adverse effects)
• Folic Acid Deficiency (complications)
• Humans
• Hyperhomocysteinemia (blood, complications, pathology, prevention & control)
• Hypertrophy
• Methionine (administration & dosage)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Papaverine (pharmacology)
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology)