Arterial hypertension and aortic remodeling in hyperhomocysteinemic mice are prevented by 3‐Deazaadenosine

Abstract

Although chronic hyperhomocysteinemia (CHHcy) is associated with arterial hypertension (AHT) and matrix metalloproteinases (MMPs) activation, it is unclear if CHHcy-dependent extracellular matrix (ECM) accumulation plays a role in AHT. We tested the hypothesis that in CHHcy, AHT involves arterial dysfunction in response to ECM accumulation between endothelial and arterial smooth muscle cells and their subsequent uncoupling. In cystathionine β-synthase knockout mice (CBSKO, a CHHcy model) increased plasma Hcy was normalized by dietary supplementation with 3-deazaadenosine (DZA), an S-adenosyl homocysteine hydrolase (SAHH) inhibitor. Mice were grouped as follows: Wild type (WT, control, n=3), CBSKO (n=3), and CBSKO+DZA (n=4). Aortic blood pressure and heart rate were monitored by radio-telemetry before, during and after DZA treatment (5 wks total). Aortic function and morphology were analyzed by M-mode and Doppler echocardiography in anesthetized mice. Total aortic MMPs activity in cryostat sections was measured by using DQ-gelatin. Expression of aortic MMP-2/MMP-9 and Connexin-43 were measured by RT-PCR and Western blot, respectively. CHHcy caused an increase in aortic blood pressure and resistance; tachycardia; increased thickness and ECM accumulation of aortic wall. In contrast, in CBSKO+DZA group; these variables were changed toward control levels. Increase in MMPs activity/expression and Connexin-43 expression in CBSKO mice was also prevented in CBSKO+DZA group. The results indicate that AHT in CHHcy mice is associated with arterial remodeling and endothelial-smooth muscle cell uncoupling in response to MMPs activation. Supported by NHLBI.