Document Detail

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice.
MedLine Citation:
PMID:  16815886     Owner:  NLM     Status:  MEDLINE    
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.
Alexander V Ovechkin; Neetu Tyagi; Utpal Sen; David Lominadze; Mesia M Steed; Karni S Moshal; Suresh C Tyagi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-06-30
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  291     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-10-10     Completed Date:  2006-11-29     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L905-11     Citation Subset:  IM    
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MeSH Terms
Antibiotics, Antineoplastic / pharmacology*
Aorta / enzymology,  pathology,  ultrasonography
Blood Pressure
Connexin 43 / genetics,  metabolism
Cystathionine beta-Synthase / genetics,  metabolism
Endothelium, Vascular / drug effects,  pathology
Extracellular Matrix / enzymology
Heart Rate
Homocysteine / blood
Hyperhomocysteinemia / complications*
Hypertension / drug therapy*,  etiology*,  physiopathology
Matrix Metalloproteinase 2 / genetics,  metabolism
Matrix Metalloproteinase 9 / genetics,  metabolism
Mice, Inbred Strains
Mice, Knockout
Muscle, Smooth, Vascular / drug effects,  pathology
Reverse Transcriptase Polymerase Chain Reaction
Tubercidin / pharmacology*
Grant Support
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Connexin 43; 0LVT1QZ0BA/Homocysteine; 6736-58-9/3-deazaadenosine; EC Metalloproteinase 2; EC Metalloproteinase 9; EC beta-Synthase; M351LCX45Y/Tubercidin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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