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Articles by R. H Boger
Total Records ( 2 ) for R. H Boger
  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.

  E Schwedhelm , V Xanthakis , R Maas , L. M Sullivan , F Schulze , U Riederer , R. A Benndorf , R. H Boger and R. S. Vasan
 

Background: Accumulating evidence links higher circulating asymmetric dimethylarginine (ADMA) to greater risk of cardiovascular disease (CVD). Relatively small differences in ADMA concentrations between healthy individuals and those with disease underscore the need to formulate reference intervals that may aid risk stratification of individuals.

Methods: We formulated reference intervals for plasma ADMA concentrations using a community-based reference sample from the Framingham Offspring Study consisting of 1126 nonsmoking individuals [mean (SD) age 56 (9) years; 60% women] who were free of clinical CVD, hypertension, diabetes, and obesity and who attended a routine examination at which ADMA was assayed. ADMA concentrations were determined using a validated tandem mass spectrometry–liquid chromatography assay.

Results: In the study sample, the mean ADMA concentration was 0.52 (0.11) µmol/L, and the reference limits were 0.311 and 0.732 (2.5th and 97.5th percentile). The sex-specific reference limits were 0.310 and 0.745 in men and 0.313 and 0.721 µmol/L in women. In multivariable regression analysis, ADMA plasma concentrations were positively correlated with age and total plasma homocysteine (both P < 0.001).

Conclusions: Reference limits calculated for circulating ADMA in our large community-based healthy reference sample confirm the previous observation of a relatively narrow distribution of concentrations. This suggests a tight physiological control of ADMA plasma concentrations, presumably by dimethylarginine dimethylaminohydrolase (DDAH) metabolism of ADMA.

 
 
 
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