Heart failure is characterized by impaired cardiac function and increased fibrosis and muscle stiffness. We showed previously that expression of transforming growth factor BETA1 (TGFBETA1) and genes encoding extracellular matrix (ECM) components is markedly upregulated during the transition from stable hypertrophy to heart failure in aged spontaneously hypertensive rats (SHR). Since matrix accumulation is influenced by angiotensin II and membrane type matrix metalloproteinases (MT-MMP), our objectives were 1) to determine whether chronic treatment with an angiotensin converting enzyme inhibitor (captopril) would prevent the increases in expression of ECM genes associated with failure, 2) to determine whether MT-MMP is expressed in rat heart, and if so, 3) whether its expression is modulated during pressure overload hypertrophy, and 4) to investigate and characterize a non-genetic model of heart failure. We studied hearts from 18-24 mo SHR with signs of failure (SHR-F), without failure (SHR-NF), SHRs treated with captopril (2g/l in drinking water) beginning at 12 mo of age (SHR-Rx) and age-matched normotensive (WKY) rats. In SHR captopril completely prevented the respective 4-fold and 1.4-fold increases in levels of beta1(III) collagen and TGFbeta1 mRNA that were exhibited by untreated SHR of advanced age. MT-MMP expression was studied in hearts of control and aortic constricted (AC) rats without failure. In hearts of young AC rats the expression of MT-MMP mRNA was elevated 1.7-fold at 1 hour post-AC and this elevation was sustained through 3 days of AC. Chronic AC of young rats was used as a non-genetic model of failure, with heart failure observed in 50% of rats by 11 mo of age. In AC rats with heart failure, TGFbeta1 mRNA levels were elevated 1.25-fold (p<0.05) compared to AC rats without failure. In contrast to the SHR model, no increase in alpha1(I) collagen or fibronectin mRNA, only a small (1.5-fold) increase in alpha1(III) collagen mRNA and a significant decrease in the level of the sarcoplasmic reticulum calcium ATPase (SERCA) mRNA were observed in failing compared to non-failing AC hearts. CONCLUSIONS: 1) Chronic captopril treatment prevented the increases in ECM gene expression that occur in untreated SHR of advanced age, suggesting a causative role for the renin-angiotensin system in fibrotic lesioning of the failing heart. 2) The rapid and sustained increase in expression of MT-MMP mRNA in hearts of AC rats implicates it in remodeling of heart. 3) Despite extensive fibrosis in AC rats with failure, the mRNA levels of ECM genes were not increased as in the SHR model, suggesting that the mechanisms underlying fibrosis differ in the two models.
