The effect of neurohumoral antagonists on the transforming growth factor ß pathway in congestive heart failure

Erwin Schrödinger Fellowship J 1958 TGF beta pathway in chronic heart failure Ingeborg SCHAFHALTER- ZOPPOTH 26.6.2000 Congestive heart failure (CHF) continues to afflict about 15 million people in the Western industrial countries and the treatment of CHF costs millions of shillings per year in Austria. Cytoldnes are an emerging new scientific field in the development of CHF. Losartan, an angiotensin II type 1 (ATI) receptor antagonist, improves -survival, decreases detrimental ventricular remodeling and reduces chronic fibrosis in the non-infarcted myocardium of coronary artery ligation rats. Bosentan, an orally available combined (ETA and ETB) receptor antagonist, also increased survival and decreased cardiac fibrosis in this heart failure model, as well as providing additional hemodynamie benefit beyond angtotensm converting enzyme inhibitor treatment. Results from previous studies suggest that transforming growth factor B (TGFbeta) is an important effector/ regulator of each of these neurohormones. TGFbeta is a cytolkine which increases cardiac fibroblast extracellular matrix (ECM) production and proliferation, as well as pathologic cardiac hypertrophy in in vitro and in vivo systems. This project will address a central hypothesis: The beneficial effects of angiotensm and endothelin antagonism on progressive chronic ventricular remodeling after myocardial infarction in rodents are partially mediated by the TGF13 signaling pathway. In order to begin to test this hypothesis, the following specific questions will be addressed: 1) Does chronic administration of losartan and/or bosentan alter the TGFB expression patterns during the development of CHF?; and 2) What is the relationship of these changes in the TGFB pathway to ventricular remodeling? The answers to these questions will provide novel information on the mechanism by which these agents effect ventricular remodeling during the evolution of heart failure.