Initiation of Cardiac Hypertrophy in Hypertension

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DESCRIPTION (provided by applicant): The goal of this renewal proposal involves a multidisciplinary integrative approach to understand the mechanism o initiation of cardiac hypertrophy. Studies from our laboratory and others have demonstrated that factors other than blood pressure control are responsible for initiating cardiac hypertrophy in hypertension. We hypothesize that cardiac hypertrophy is initiated by a signal, either mechanical or humoral, to the myocardium and that the myocardium in turn produces a factor that triggers protein synthesis. We have identified the factor myotrophin from spontaneously hypertensive rat hearts (SHR). This 12.5-kD factor, which stimulates myocyte growth, has been purified to homogeneity, sequenced, and cloned. We have shown that myotrophin increases transcript levels of proto-oncogenes, stimulates transcript levels of B-myosin heavy chain and ANF levels of myotrophin in both SHR and human hearts. All our findings have provided a wealth of convincing evidence that myotrophin plays an important role in stimulating myocyte growth. Our most recent achievement was the development of a transgenic mouse model overexpressing myotrophin in the heart. Specific overexpression of myotrophin, as measured by both mRNA and proteins, in the myocardium resulted in cardiomyopathy that advanced to heart failure. Cardiac hypertrophy was associated with multiple focal fibrosis, myocyte necrosis and significant reduction of ejection fraction. The development of this transgenic mouse model has opened up new doors to study not only the initiation process of hypertrophy but also to follow molecular changes that occur at specific points during the transition of hypertrophy to heart failure. More importantly, our data showed that myotrophin overexpression resulted in the development of hypertrophy that advances to heart failure. Now, we are focusing on how myotrophin exerts its effect on myocyte growth and the molecular changes that take place during initiation of hypertrophy to its advancement to heart failure. We propose a combination of molecular, genetic, cellular and pathophysiological approaches. Our specific aims are (1) to study molecular changes that occur in the transgenic mouse model overexpressing myotrophin, analyzing changes that occur as a consequence of myotrophin, especially during progression of hypertrophy to heart failure; (2) to elucidate steps in the signaling pathway activated by myotrophin overexpression that lead to heart failure; (3) to intervene pharmacologically to prevent/regress cardiac hypertrophy at various points; (4) to define, by echocardiography, the cardiac functions correlated with the molecular changes observed in the above experiments. The results expected from this study are directly related to problems of human hypertension and hypertrophy, as the molecular changes observed are very similar to those seen in human cardiomyopathy. The proposed experiments will improve our understanding of myotrophin's mechanism of action and its pathophysiological significance. Our studies may lead to the development of therapeutic tools for controlling or preventing the development of hypertrophy and heart failure in human hearts.