RGD Reference Report - 3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice. - Rat Genome Database

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3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice.

Authors: Ovechkin, AV  Tyagi, N  Sen, U  Lominadze, D  Steed, MM  Moshal, KS  Tyagi, SC 
Citation: Ovechkin AV, etal., Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L905-11. Epub 2006 Jun 30.
RGD ID: 1601153
Pubmed: PMID:16815886   (View Abstract at PubMed)
PMCID: PMC3182487   (View Article at PubMed Central)
DOI: DOI:10.1152/ajplung.00543.2005   (Journal Full-text)

Chronic hyperhomocysteinemia (HHcy) is an important factor in development of arterial hypertension. HHcy is associated with activation of matrix metalloproteinases (MMPs); however, it is unclear whether HHcy-dependent extracellular matrix (ECM) accumulation plays a role in arterial hypertrophy and hypertension. We tested the hypothesis that in HHcy the mechanism of arterial hypertension involves arterial dysfunction in response to ECM accumulation between endothelial and arterial smooth muscle cells and subsequent endothelium-myocyte (E-M) uncoupling. To decrease plasma Hcy, dietary supplementation with 3-deazaadenosine (DZA), the S-adenosylhomocysteine hydrolase inhibitor, was administered to cystathionine beta-synthase (CBS) knockout (KO) mice. Mice were grouped as follows: wild type (WT; control), WT+DZA, CBSKO, and CBSKO+DZA (n = 4/group). Mean aortic blood pressure and heart rate were monitored in real time with a telemetric system before, during, and after DZA treatment (6 wk total). In vivo aorta function and morphology were analyzed by M-mode and Doppler echocardiography in anesthetized mice. Aorta MMP activity in unfixed cryostat sections was measured with DQ gelatin. Aorta MMP-2, MMP-9, and connexin 43 expression were measured by RT-PCR and Western blot analyses, respectively. HHcy caused increased aortic blood pressure and resistance, tachycardia, and increased wall thickness and ECM accumulation in aortic wall vs. control groups. There was a linear correlation between aortic wall thickness and plasma Hcy levels. MMP-2, MMP-9, and connexin 43 expression were increased in HHcy. In the CBSKO+DZA group, aortic blood pressure and levels of MMP and connexin 43 were close to those found in control groups. However, removal of DZA reversed the aortic lumen-to-wall thickness ratio in CBSKO mice, suggesting, in part, a role of vascular remodeling in the increase in blood pressure in HHcy. The results show that arterial hypertension in HHcy mice is, in part, associated with arterial remodeling and E-M uncoupling in response to MMP activation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypertension  ISOAhcy (Mus musculus)1601153; 1601153associated with hyperhomocysteinemiaRGD 
hypertension  IMP 1601153associated with hyperhomocysteinemiaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ahcy  (adenosylhomocysteinase)

Genes (Mus musculus)
Ahcy  (S-adenosylhomocysteine hydrolase)

Genes (Homo sapiens)
AHCY  (adenosylhomocysteinase)


Additional Information