| 3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice. | |
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MedLine Citation:
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PMID: 16815886 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Alexander V Ovechkin; Neetu Tyagi; Utpal Sen; David Lominadze; Mesia M Steed; Karni S Moshal; Suresh C Tyagi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2006-06-30 |
Journal Detail:
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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:
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Created Date: 2006-10-10 Completed Date: 2006-11-29 Revised Date: 2012-04-27 |
Medline Journal Info:
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Nlm Unique ID: 100901229 Medline TA: Am J Physiol Lung Cell Mol Physiol Country: United States |
Other Details:
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Languages: eng Pagination: L905-11 Citation Subset: IM |
Affiliation:
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Department of Physiology & Biophysics, Health Sciences Center A-1115, School of Medicine, University of Louisville, KY 40202, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibiotics, Antineoplastic / pharmacology* Aorta / enzymology, pathology, ultrasonography Blood Pressure Connexin 43 / genetics, metabolism Cystathionine beta-Synthase / genetics, metabolism Echocardiography Endothelium, Vascular / drug effects, pathology Extracellular Matrix / enzymology Female Heart Rate Homocysteine / blood Hyperhomocysteinemia / complications* Hypertension / drug therapy*, etiology*, physiopathology Male Matrix Metalloproteinase 2 / genetics, metabolism Matrix Metalloproteinase 9 / genetics, metabolism Mice Mice, Inbred Strains Mice, Knockout Muscle, Smooth, Vascular / drug effects, pathology Reverse Transcriptase Polymerase Chain Reaction Tubercidin / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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HL-71010/HL/NHLBI NIH HHS; HL-74185/HL/NHLBI NIH HHS; R01 HL080394-01A2/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Connexin 43; 454-28-4/Homocysteine; 6736-58-9/3-deazaadenosine; 69-33-0/Tubercidin; EC 3.4.24.24/Matrix Metalloproteinase 2; EC 3.4.24.35/Matrix Metalloproteinase 9; EC 4.2.1.22/Cystathionine beta-Synthase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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