Overexpression of Dimethylarginine Dimethylaminohydrolase Protects Against Cerebral Vascular Effects of Hyperhomocysteinemia

• Published in: Circulation research Vol. 106; no. 3; pp. 551 - 558
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 19.02.2010; Lippincott Williams & Wilkins
• Subjects: Acetylcholine - pharmacology; Amidohydrolases - genetics; Amidohydrolases - physiology; Animals; Arginine - analogs & derivatives; Arginine - blood; Arterioles - pathology; Biological and medical sciences; Carotid Artery Thrombosis - etiology; Cerebral Arterial Diseases - etiology; Cerebral Arterial Diseases - prevention & control; Diet - adverse effects; Folic Acid Deficiency - complications; Fundamental and applied biological sciences. Psychology; Humans; Hyperhomocysteinemia - blood; Hyperhomocysteinemia - complications; Hyperhomocysteinemia - pathology; Hyperhomocysteinemia - prevention & control; Hypertrophy; Methionine - administration & dosage; Mice; Mice, Inbred C57BL; Mice, Transgenic; Papaverine - pharmacology; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system; Enzyme; Central nervous system; amino acids; Gene overexpression; Cardiovascular disease; Thrombosis; Nitric-oxide synthase; Vasodilation; Encephalon; Endothelium; Vascular disease; Vasomotricity; Vertebrata; Mammalia; Aminoacid; Hyperhomocysteinemia; Oxidoreductases; Circulatory system; nitric oxide synthase
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.200360

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.