Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia

Sanjana Dayal; Roman N Rodionov; Erland Arning; Teodoro Bottiglieri; Masumi Kimoto; Daryl J Murry; John P Cooke; Frank M Faraci; Steven R Lentz

doi:10.1152/ajpheart.01348.2007

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Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia

Journal article

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Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia

Sanjana Dayal, Roman N Rodionov, Erland Arning, Teodoro Bottiglieri, Masumi Kimoto, Daryl J Murry, John P Cooke, Frank M Faraci and Steven R Lentz

American journal of physiology. Heart and circulatory physiology, Vol.295(2), pp.H816-H825

08/2008

DOI: 10.1152/ajpheart.01348.2007

PMCID: PMC2519228

PMID: 18567702

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Abstract

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, has been proposed to be a mediator of vascular dysfunction during hyperhomocysteinemia. Levels of ADMA are regulated by dimethylarginine dimethylaminohydrolase (DDAH). Using both in vitro and in vivo approaches, we tested the hypothesis that hyperhomocysteinemia causes downregulation of the two genes encoding DDAH ( Ddah1 and Ddah2 ). In the MS-1 murine endothelial cell line, the addition of homocysteine decreased NO production but did not elevate ADMA or alter levels of Ddah1 or Ddah2 mRNA. Mice heterozygous for cystathionine β-synthase ( Cbs ) and their wild-type littermates were fed either a control diet or a high-methionine/low-folate (HM/LF) diet to produce varying degrees of hyperhomocysteinemia. Maximal relaxation of the carotid artery to the endothelium-dependent dilator acetylcholine was decreased by ∼50% in Cbs +/− mice fed the HM/LF diet compared with Cbs +/+ mice fed the control diet ( P < 0.001). Compared with control mice, hyperhomocysteinemic mice had lower levels of Ddah1 mRNA in the liver ( P < 0.001) and lower levels of Ddah2 mRNA in the liver, lung, and kidney ( P < 0.05). Downregulation of DDAH expression in hyperhomocysteinemic mice did not result in an increase in plasma ADMA, possibly due to a large decrease in hepatic methylation capacity ( S -adenosylmethionine-to- S -adenosylhomocysteine ratio). Our findings demonstrate that hyperhomocysteinemia causes tissue-specific decreases in DDAH expression without altering plasma ADMA levels in mice with endothelial dysfunction.

homocysteine

endothelium

vascular function

asymmetric dimethylarginine

Details

Title: Subtitle: Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia
Creators: Sanjana Dayal - Departments of
Roman N Rodionov - Departments of
Erland Arning - Departments of
Teodoro Bottiglieri - Departments of
Masumi Kimoto - Departments of
Daryl J Murry - Departments of
John P Cooke - Departments of
Frank M Faraci - Departments of
Steven R Lentz - Departments of
Resource Type: Journal article
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.295(2), pp.H816-H825
DOI: 10.1152/ajpheart.01348.2007
PMID: 18567702
PMCID: PMC2519228
NLM abbreviation: Am J Physiol Heart Circ Physiol
ISSN: 0363-6135
eISSN: 1522-1539
Publisher: American Physiological Society
Language: English
Date published: 08/2008
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Holden Comprehensive Cancer Center; Internal Medicine
Record Identifier: 9984040013102771

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