Chronic AT(1) blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats

It has been suggested that left ventricular fibrosis in spontaneously hyper tensive rats (SHR) is the result of both exaggerated collagen synthesis and insufficient collagen degradation. We have shown previously that chronic t reatment with the angiotensin II type 1 receptor antagonist losartan result s in diminished synthesis of collagen type I molecules and reversal of myoc ardial fibrosis in SHR, This study was designed to investigate whether losa rtan also affects the extracellular degradation of collagen type I fibers i n the left ventricle of SHR. The study was performed in 30-week-old normote nsive Wistar-Kyoto rats (WKY), untreated SHR, and SHR treated with orally a dministered losartan (20 mg/kg per day) for 14 weeks before they were kille d. Ventricular collagenase activity was determined by degradation of [C-14] collagen with tissue extracts, Ventricular expression of tissue inhibitor o f metalloproteinases 1 (TIMP-1) mRNA was analyzed by Northern blot, A histo morphometric study of the left ventricle was performed in all rats. Compare d with WKY, SHR exhibited left ventricular hypertrophy, increased (P<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and diminished (P<0.05) collagenase activity. After the treatment period, b lood pressure was higher (P<0.05) in losartan-treated SHR than in WKY, and no significant differences were noted in the remaining parameters between t he 2 strains of rats. Compared with untreated SHR, treated SHR showed no le ft ventricular hypertrophy, diminished (P<0.05) blood pressure, left ventri cular collagen volume fraction and TIMP-1 mRNA, and increased (P<0.05) coll agenase activity. These results suggest that the transcription of the TIMP- 1 gene is upregulated in the hypertrophied and fibrotic left ventricle of a dult SHR, Upregulation of TIMP-1 may account for diminished collagenase act ivity in the myocardium of those rats. Chronic angiotensin II type 1 recept or blockade with losartan resulted in inhibition of TIMP-1 expression and s timulation of collagenase activity in the left ventricle of SHR. It is prop osed that angiotensin II may facilitate myocardial fibrosis in SHR by depre ssing the collagenase-mediated extracellular degradation of collagen fibers .