OF WORK Heart failure in aged, spontaneously hypertensive rats (SHR) is characterized by impaired cardiac function, increased fibrosis and muscle stiffness. We showed previously that expression of genes encoding extracellular matrix (ECM) components is markedly upregulated during the transition from stable hypertrophy to heart failure in aged SHR. Further, we showed that chronic captopril treatment prevents 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. Since the renin-angiotensin system consists of both sytemic and local components, we tested the hypotheses that 1) heart failure would be associated with alterations in the expression of renin and angiotensinogen (Ao) nRNA in the heart ventricles, and 2) chronic angiotensin converting enzyme inhibition (ACEI) therapy would modulate the failure-associated changes in renin and Ao mRNA expression. Methods: We studied hearts from 18-24 mo SHR with signs of failure (SHR- F), without failure (SHR-NF), SHRs treated with captopril beginning at 12, 18 or 21 mo of age (SHR-Rx) or after signs of failure were evident (SHR-F-Rx) and age-matched normotensive (WKY) rats. Levels of left ventricular renin and Ao mRNA were determined by a quantitative PCR approach. Results: Left ventricular levels of renin mRNA did not differ between untreated age-matched SHR-F, SHR-NF or WKY groups. Chronic ACEI elevated the level of LV renin mRNA 2-4-fold compared to that of untreated rats. The magnitude of the increase in renin mRNA level in SHR was related to the length of captopril treatment. Ao mRNA levels were significantly decreased in SHR-F compared to either WKY or SHR-NF, and were not significantly altered by any of the captopril-treatment regimens. Conclusions: Expression of renin and Ao genes in the hearts of SHR is discoordinately regulated during the transition from stable hypertrophy to heart failure and is effected differently by ACEI, suggesting that these closely related genes are subject to different control mechanisms in the heart. Significance: Chronic heart failure is the leading hospital discharge diagnosis in the United States, and as such represents a major health burden. Our work with the SHR has demonstrated the utility of this model for studying putative mechanisms of heart failure. Proposed Course: The mechanism(s) of the therapeutic benefits derived from the ACE inhibitor are not known, but may be mediated by multiple effects of captopril involving both circulating and local RAS components and including actions at the angiotensin (AT) and bradykinin receptors.
Our specific aim i s to distinguish the role of AT1, AT2 and bradykinin B2 receptors in the ACEI-mediated effects on survival, heart function, gene expression and apoptotic processes in the SHR model of heart failure.
