Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro laboratory study with no human data
PubMed 18567702 · doi:10.1152/ajpheart.01348.2007
What was done
The authors examined whether hyperhomocysteinemia downregulates dimethylarginine dimethylaminohydrolase genes (Ddah1 and Ddah2) in cell culture and mouse models. In vitro, MS-1 murine endothelial cells were exposed to homocysteine to measure nitric oxide (NO) production, asymmetric dimethylarginine (ADMA) levels, and Ddah expression. In vivo, wild-type (Cbs+/+) and heterozygous cystathionine beta-synthase-deficient (Cbs+/-) mice were fed either a control diet or a high-methionine/low-folate diet to induce hyperhomocysteinemia. Outcomes included carotid artery relaxation to acetylcholine, tissue-specific Ddah mRNA levels in liver, lung, and kidney, and plasma ADMA concentrations.
What was found
In MS-1 endothelial cells, homocysteine decreased NO production without altering ADMA, Ddah1, or Ddah2 mRNA levels. In vivo, maximal carotid artery relaxation to acetylcholine was reduced by approximately 50% in Cbs(+/-) mice on the high-methionine/low-folate diet compared with Cbs(+/+) controls (P < 0.001). Hyperhomocysteinemic mice had lower liver Ddah1 mRNA (P < 0.001) and lower Ddah2 mRNA in liver, lung, and kidney (P < 0.05). Plasma ADMA levels were not increased in hyperhomocysteinemic mice despite DDAH downregulation.
Why it matters
The findings demonstrate that hyperhomocysteinemia leads to tissue-specific DDAH downregulation and endothelial dysfunction independently of increases in circulating ADMA, questioning the concept that plasma ADMA elevation is necessary for homocysteine-induced vascular impairment.
Limits
The study is limited to an animal model and cell culture, which may not replicate human cardiovascular biology. Sample sizes (n) were not reported in the abstract. DDAH protein levels and direct enzyme activity were not detailed in the abstract.
Cited by
- partial Elevated homocysteine impairs the clearance of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA).