PMID- 16815886 OWN - NLM STAT- MEDLINE DCOM- 20061129 LR - 20200930 IS - 1040-0605 (Print) IS - 1522-1504 (Electronic) IS - 1040-0605 (Linking) VI - 291 IP - 5 DP - 2006 Nov TI - 3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice. PG - L905-11 AB - 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. FAU - Ovechkin, Alexander V AU - Ovechkin AV AD - Department of Physiology & Biophysics, Health Sciences Center A-1115, School of Medicine, University of Louisville, KY 40202, USA. FAU - Tyagi, Neetu AU - Tyagi N FAU - Sen, Utpal AU - Sen U FAU - Lominadze, David AU - Lominadze D FAU - Steed, Mesia M AU - Steed MM FAU - Moshal, Karni S AU - Moshal KS FAU - Tyagi, Suresh C AU - Tyagi SC LA - eng GR - R01 HL074185/HL/NHLBI NIH HHS/United States GR - R01 HL080394-01A2/HL/NHLBI NIH HHS/United States GR - R01 HL080394/HL/NHLBI NIH HHS/United States GR - R01 HL071010/HL/NHLBI NIH HHS/United States GR - HL-74185/HL/NHLBI NIH HHS/United States GR - HL-71010/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20060630 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Connexin 43) RN - 037V4520IY (3-deazaadenosine) RN - 0LVT1QZ0BA (Homocysteine) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) RN - M351LCX45Y (Tubercidin) SB - IM MH - Animals MH - Antibiotics, Antineoplastic/*pharmacology MH - Aorta/diagnostic imaging/enzymology/pathology MH - Blood Pressure MH - Connexin 43/genetics/metabolism MH - Cystathionine beta-Synthase/genetics/metabolism MH - Echocardiography MH - Endothelium, Vascular/drug effects/pathology MH - Extracellular Matrix/enzymology MH - Female MH - Heart Rate MH - Homocysteine/blood MH - Hyperhomocysteinemia/*complications MH - Hypertension/*drug therapy/*etiology/physiopathology MH - Male MH - Matrix Metalloproteinase 2/genetics/metabolism MH - Matrix Metalloproteinase 9/genetics/metabolism MH - Mice MH - Mice, Inbred Strains MH - Mice, Knockout MH - Muscle, Smooth, Vascular/drug effects/pathology MH - Reverse Transcriptase Polymerase Chain Reaction MH - Tubercidin/*pharmacology PMC - PMC3182487 MID - NIHMS169033 EDAT- 2006/07/04 09:00 MHDA- 2006/12/09 09:00 PMCR- 2011/09/29 CRDT- 2006/07/04 09:00 PHST- 2006/07/04 09:00 [pubmed] PHST- 2006/12/09 09:00 [medline] PHST- 2006/07/04 09:00 [entrez] PHST- 2011/09/29 00:00 [pmc-release] AID - 00543.2005 [pii] AID - 10.1152/ajplung.00543.2005 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L905-11. doi: 10.1152/ajplung.00543.2005. Epub 2006 Jun 30.