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3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice
Alexander V Ovechkin1, Neetu Tyagi, Utpal Sen
1Department of Physiology & Biophysics, Health Sciences Center A-1115, School of Medicine, University of Louisville, KY 40202, USA.
Insights
Chronic hyperhomocysteinemia (HHcy) causes arterial hypertension by increasing extracellular matrix accumulation and activating matrix metalloproteinases (MMPs). This leads to arterial remodeling and endothelium-myocyte uncoupling.
Area of Science:
- Cardiovascular Research
- Hypertension Pathophysiology
- Vascular Biology
Background:
- Chronic hyperhomocysteinemia (HHcy) is linked to arterial hypertension.
- Matrix metalloproteinases (MMPs) are activated in HHcy, but their role in HHcy-induced vascular changes is unclear.
- Extracellular matrix (ECM) accumulation may contribute to arterial hypertrophy and hypertension in HHcy.
Purpose of the Study:
- To test if HHcy-induced arterial hypertension involves ECM accumulation and endothelium-myocyte (E-M) uncoupling.
- To investigate the role of MMPs in HHcy-associated vascular remodeling.
- To evaluate the therapeutic potential of reducing homocysteine levels.
Main Methods:
- Cystathionine beta-synthase (CBS) knockout (KO) mice were treated with 3-deazaadenosine (DZA) to reduce plasma homocysteine (Hcy).
- Blood pressure, heart rate, and aortic function/morphology were monitored telemetrically and via echocardiography.
- MMP activity, MMP-2, MMP-9, and connexin 43 expression were analyzed in aortic tissues.
Main Results:
- HHcy mice exhibited increased blood pressure, heart rate, aortic wall thickness, and ECM accumulation.
- A linear correlation was observed between aortic wall thickness and plasma Hcy levels.
- MMP-2, MMP-9, and connexin 43 expression were elevated in HHcy, and DZA treatment normalized these parameters.
Conclusions:
- Arterial hypertension in HHcy is partly mediated by arterial remodeling and E-M uncoupling.
- MMP activation plays a significant role in HHcy-induced vascular changes.
- Reducing Hcy levels can ameliorate vascular remodeling and hypertension in HHcy.
Abstract:
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.
