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Mounting evidence indicates that structural and functional vascular changes associated with two-kidney, one-clip (2K-1C) hypertension result, at least in part, from altered activity of matrix metalloproteinases (MMPs). Because MMPs are upregulated by increased formation of reactive oxygen species (ROS), we hypothesized that antioxidant approaches could attenuate the increases in MMP-2 expression/activity and the vascular dysfunction and remodeling associated with 2K-1C hypertension. Sham-operated or 2K-1C hypertensive rats were treated with tempol 18 mg/kg/day or apocyanin 25 mg/kg/day (or vehicle). Systolic blood pressure was monitored weekly. After 8 weeks of treatment, aortic rings were isolated to assess endothelium-dependent and -independent relaxation. Quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin sections. Aortic and systemic ROS levels were measured using dihydroethidine and thiobarbituric acid-reactive substances, respectively. Aortic MMP-2 levels and activity were determined by gelatin and in situ zymography, fluorimetry, and immunohistochemistry. Tempol and apocyanin attenuated 2K-1C hypertension (181+/-20.8 and 192+/-17.6 mm Hg, respectively, versus 213+/-18 mm Hg in hypertensive controls; both p<0.05) and prevented the reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Tempol, but not apocyanin (p>0.05), prevented the vascular remodeling found in 2K-1C rats (all p<0.01). Tempol was more effective than apocyanin in attenuating hypertension-induced increases in oxidative stress (both p<0.05), MMP-2 levels, and MMP-2 activity in hypertensive rats (all p<0.05). Our results suggest that antioxidant approaches decrease MMP-2 upregulation and attenuate the vascular dysfunction and remodeling during 2K-1C hypertension.

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SPRL or HCTZ, alone or combined, exerted antioxidant effects, and decreased renovascular hypertension-induced MMP-2 up-regulation, thus improving the vascular dysfunction and remodelling found in this model of hypertension.

Hypertension induces vascular alterations that are associated with up-regulation of matrix metalloproteinases (MMPs). While these alterations may be blunted by doxycycline, a non-selective MMPs inhibitor, no previous study has examined the effects of different doses of doxycycline on these alterations. This is important because doxycycline has been used at sub-antimicrobial doses, and the use of lower doses may prevent the emergence of antibiotic-resistant microorganisms. We studied the effects of doxycycline at 3, 10 and 30 mg ⁄ kg per day on the vascular alterations found in the rat two kidneyone clip (2K1C) hypertension (n = 20 rats ⁄ group). Systolic blood pressure (SBP) was monitored during 4 weeks of treatment.We assessed endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes in the aortic wall was studied, and aortic MMP-2 levels ⁄ proteolytic activity were determined by gelatin and in situ zymography, respectively. All treatments attenuated the increases in SBP in hypertensive rats (195.4 € 3.9 versus 177.2 € 6.2, 176.3 € 4.5, and 173 € 5.1 mmHg in 2K1C hypertensive rats treated with vehicle, or doxycycline at 3, 10, 30 mg ⁄ kg per day, respectively (all p < 0.01). However, only the highest dose prevented 2K1C-induced reduction in endothelium-dependent vasorelaxation (p < 0.05), vascular hypertrophy and increases in MMP-2 levels (all p < 0.05). In conclusion, our results suggest that relatively lower doses of doxycycline do not attenuate the vascular alterations found in the 2K1C hypertension model, and only the highest dose of doxycycline affects MMPs and vascular structure. Our results support the idea that the effects of doxycycline on MMP-2 and vascular structure are pressure independent.Hypertension is a major cardiovascular disease that is associated with vascular remodelling characterized by degradation and reorganization of extracellular matrix in the vessel wall [1]. Vascular remodelling is an adaptive response to elevation of arterial pressure to normalize the wall tension [2] and has been clearly described in experimental models of hypertension, including the 2-kidney, 1-clip (2K1C) Goldblatt model, which involves the activation of the renin-angiotensin-aldosterone axis [3,4].Metalloproteinases (MMPs) are zinc-containing enzymes that play important roles in cardiovascular diseases [5]. Upregulated MMPs promote excessive degradation of extracellular matrix and are involved in pathological vascular remodelling [6], which includes vascular smooth muscle cell migration and proliferation in the arterial wall [7]. In fact, increased expression and activity of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) have been consistently implicated in vascular remodelling associated with hypertension in patients [8,9] and animal models [10][11][12][13][14][15][16]. We have recently found evidence suggesting that enhanced aortic MMP-2 levels and activity may underlie the impaired endothelial-dependent vasorelaxation, arterial wall hypertrophy, and excessive c...