Cardiovascular remodeling found in later phases of two-kidney, one-
clip (2K1C)
hypertension may involve key mechanisms particularly including MMP-2, oxidative stress,
transforming growth factor-β (TGF-β), and inactivation of the endogenous
MMP inhibitor, the tissue inhibitor of
MMP (TIMP)-4. We examined whether temporal cardiac remodeling resulting from 2K1C
hypertension occurs concomitantly with alterations in cardiac
collagen,
MMP activity, MMP-2, TIMP-4, TGF-β, and
reactive oxygen species (ROS) levels during the development of 2K1C
hypertension.
Sham-operated and 2K1C hypertensive rats were studied after 15, 30, and 75 days of
hypertension. Systolic blood pressure was monitored weekly. Left ventricle (LV) morphometry and
fibrosis were evaluated in
hematoxylin/
eosin and
picrosirius red-stained sections, respectively. Cardiac MMP-2 levels/activity was determined by
gelatin zymography, immunofluorescence, and in situ zymography. TIMP-4 levels were determined by western blotting. Cardiac TGF-β levels were evaluated by immunofluorescence and ROS levels were evaluated with a
dihydroethidium probe. 2K1C
hypertension induced LV
hypertrophy associated with augmented gelatinolytic activity at an early phase of
hypertension and further increased after 75 days of
hypertension. These alterations were associated with increased cardiac MMP-2, TGF-β, and ROS in hypertensive rats. Higher TIMP-4 levels were found in hypertensive rats only after 75 days after surgery. Our findings show that increased MMP-2 activity is associated with concomitant development of LV
hypertrophy and increased TGF-β and ROS levels.