Temporal changes in cardiac matrix metalloproteinase activity, oxidative stress, and TGF-β in renovascular hypertension-induced cardiac hypertrophy

Abstract

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 75days 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 75days 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 75days 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.