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.
RATIONALE: Hyperhomocysteinemia is a cardiovascular risk factor that is associated with elevation of the nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA). OBJECTIVE: Using micetransgenic 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 DDAH1transgenic (DDAH1Tg) 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 DDAH1Tgmice fed the HM/LF diet compared with the control diet (P<0.001). Plasma ADMA was approximately 40% lower in DDAH1Tgmice 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 DDAH1Tg (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 DDAH1Tgmice (45 + or - 7 versus 48 + or - 6%). DDAH1Tgmice 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: Martin den Heijer; Huub P J Willems; Henk J Blom; Wim B J Gerrits; Marco Cattaneo; Sabine Eichinger; Frits R Rosendaal; Gerard M J Bos Journal: Blood Date: 2006-09-07 Impact factor: 22.113
Authors: Hayan Dayoub; Roman N Rodionov; Cynthia Lynch; John P Cooke; Erland Arning; Teodoro Bottiglieri; Steven R Lentz; Frank M Faraci Journal: Stroke Date: 2007-12-06 Impact factor: 7.914
Authors: Christine M Albert; Nancy R Cook; J Michael Gaziano; Elaine Zaharris; Jean MacFadyen; Eleanor Danielson; Julie E Buring; JoAnn E Manson Journal: JAMA Date: 2008-05-07 Impact factor: 56.272
Authors: Rex L Jamison; Pamela Hartigan; James S Kaufman; David S Goldfarb; Stuart R Warren; Peter D Guarino; J Michael Gaziano Journal: JAMA Date: 2007-09-12 Impact factor: 56.272
Authors: Karen Horsburgh; Joanna M Wardlaw; Tom van Agtmael; Stuart M Allan; Mike L J Ashford; Philip M Bath; Rosalind Brown; Jason Berwick; M Zameel Cader; Roxana O Carare; John B Davis; Jessica Duncombe; Tracy D Farr; Jill H Fowler; Jozien Goense; Alessandra Granata; Catherine N Hall; Atticus H Hainsworth; Adam Harvey; Cheryl A Hawkes; Anne Joutel; Rajesh N Kalaria; Patrick G Kehoe; Catherine B Lawrence; Andy Lockhart; Seth Love; Malcolm R Macleod; I Mhairi Macrae; Hugh S Markus; Chris McCabe; Barry W McColl; Paul J Meakin; Alyson Miller; Maiken Nedergaard; Michael O'Sullivan; Terry J Quinn; Rikesh Rajani; Lisa M Saksida; Colin Smith; Kenneth J Smith; Rhian M Touyz; Rebecca C Trueman; Tao Wang; Anna Williams; Steven C R Williams; Lorraine M Work Journal: Clin Sci (Lond) Date: 2018-04-30 Impact factor: 6.124