3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice

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 ␤-synthase (CBS) knockout (KO) mice. Mice were grouped as follows: wild type (WT; control), WTϩDZA, CBSKO, and CBSKOϩDZA (n ϭ 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 CBSKOϩDZA 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. cardiovascular dysfunction; aorta; echocardiography; extracellular matrix remodeling; in situ matrix metalloproteinase activity; cystathionine ␤-synthase; connexin; DQ gelatin; telemetry EXPERIMENTAL AND CLINICAL studies have shown that chronic elevation of homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), is a significant independent risk factor for cardiovascular disease (31), particularly in the development of arterial hypertension and atherosclerosis (3,24,26). The mechanisms by which HHcy affects arterial wall and induces arterial hypertension have remained unclear. It has been shown that HHcy leads to arterial damage (4) and increased arterial wall stiffness (2,22).Hcy is a product of methionine metabolism that under normal conditions is converted to cystathionine by cystathionine ␤-synthase (CBS). It has been established that mice carrying a disrupted CBS gene are adequate models for HHcy. Systemic vascular cells lacking CBS (7,8) are the prime target for...

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Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

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