INITIATION OF CARDIAC HYPERTROPHY IN HYPERTENSION

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DESCRIPTION (Adapted from Investigator's Abstract): In a study designed to elucidate factors other than blood pressure which are responsible for development of cardiac growth and myocardial hypertrophy, the investigator has hypothesized that cardiac hypertrophy is initiated by a mechanical or humoral signal to the myocardium, which in turn produces a soluble factor, previously identified by this laboratory as a 12 kD protein called myotrophin. This substance has been identified in SHR, other rat models of cardiac hypertrophy, and in human dilated cardiomyopathy. When added to isolated cardiac myocytes, myotrophin triggers protein synthesis. Myotrophin has been cloned, stimulates production of hypertrophy markers such as c-myc, c-fos, c-jun, ANF, beta-MHC and connexin and may play a role in myocyte growth. Multiple transcripts have been identified in SHR which all express a 12 kD protein. ECHO methods have been developed to follow functional and morphologic alterations in mice. In the present application, molecular, genetic and functional approaches will be used to understand the mode of action of myotrophin with the following specific aims: a) to elucidate the signal transduction mechanisms by which myotrophin stimulates protein synthesis; b) to study the effect of mechanical stretch on release of myotrophin; c) to localize myotrophin and study its effect on myocyte morphology; d) to use transgenic mice to study the effect of overexpression of myotrophin, determine its effects at the cellular and molecular level, and compare those data with data on cardiac function; e) to evaluate functions in mice by a noninvasive ECHO and Doppler technique to establish whether overexpression of myotrophin results in a physiological or pathophysiological hypertrophy. Long term goals are to elucidate mechanisms for translation of cardiac load and myocardial stress into biochemical messages prompting protein synthesis, and to develop strategies to prevent diseases associated with severe cardiac hypertrophy.