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Articles by M Kimoto
Total Records ( 2 ) for M Kimoto
  X Hu , X Xu , G Zhu , D Atzler , M Kimoto , J Chen , E Schwedhelm , N Luneburg , R. H Boger , P Zhang and Y. Chen
 

Background— Asymmetrical methylarginines inhibit NO synthase activity and thereby decrease NO production. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) degrades asymmetrical methylarginines. We previously demonstrated that in the heart DDAH1 is predominantly expressed in vascular endothelial cells. Because an earlier study showed that mice with global DDAH1 deficiency experienced embryonic lethality, we speculated that a mouse strain with selective vascular endothelial DDAH1 deficiency (endo-DDAH1–/–) would largely abolish tissue DDAH1 expression in many tissues but possibly avoid embryonic lethality.

Methods and Results— By using the LoxP/Cre approach, we generated the endo-DDAH1–/– mice. The endo-DDAH1–/– mice had no apparent defect in growth or development compared with wild-type littermates. DDAH1 expression was greatly reduced in kidney, lung, brain, and liver, indicating that in these organs DDAH1 is distributed mainly in vascular endothelial cells. The endo-DDAH1–/– mice showed a significant increase of asymmetric dimethylarginine concentration in plasma (1.41 µmol/L in the endo-DDAH1–/– versus 0.69 µmol/L in the control mice), kidney, lung, and liver, which was associated with significantly increased systolic blood pressure (132 mm Hg versus 113 mm Hg in wild-type). The endo-DDAH1–/– mice also exhibited significantly attenuated acetylcholine-induced NO production and vessel relaxation in isolated aortic rings.

Conclusions— Our study demonstrates that DDAH1 is highly expressed in vascular endothelium and that endothelial DDAH1 plays an important role in regulating blood pressure. In the context that asymmetric methylarginines are broadly produced by many type of cells, the strong DDAH1 expression in vascular endothelium demonstrates for the first time that vascular endothelium can be an important site to actively dispose of toxic biochemical molecules produced by other types of cells.

  R. N Rodionov , H Dayoub , C. M Lynch , K. M Wilson , J. W Stevens , D. J Murry , M Kimoto , E Arning , T Bottiglieri , J. P Cooke , G. L Baumbach , F. M Faraci and S. R. Lentz
 

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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