What are the initial events leading to the different cardiac hypertrophies in hypertension and valvular insufficiency? The present proposal is designed to investigate the initial stimuli, sequence of events, and protein synthesis in these stresses so that we may examine the paths the heart takes towards hypertrophy when subjected to excessive pre- or afterload. Furthermore, since the synthetic processes may be affected by aging and the common stresses of ischemia and chronic ethanol exposure, the proposal will also direct attention to the combination of the above on cardiac protein synthesis. The project will have 3 main objectives: (1) The response of cardiac nuclei to acute hemodynamic overload; (2) the synthesis of specific cardiac proteins in such overload and the effects of oxygen deprivation and of aging; (3) chronic ethanol exposure and cardiac protein metabolism. The studies of the nuclear response will ask (a) What are the factors in cytosol required for the increases in nuclear RNA polymerase II activity rapidly induced by application of pressure? (b) Is there increase in DNA template activity in the nuclei due to pressure? (c) What is the role of nucleoproteins in the response to pressure overload? (d) Do nuclei from aged hearts respond in the same fashion as those taken from the young? (e) Do nuclei from preloaded hearts differ in their response? The studies of specific cardiac proteins (contractile, connective & respiratory) will attempt to answer the questions (a) How does oxygen deprivation influence the response to hemodynamic overload? (b) Howe does oxygen deprivation influence the response in different age groups? (c) What proteins are affected by preload? The effect of chronic ethanol ingestion will be examined by (a) studies of synthesis of specific proteins after prolonged ethanol ingestion in the maturing and aging animal; (b) after introduction of additional stresses as relative ischemia and overload; and (c) by studies of cardiac protein degradation after prolonged ethanol ingestion. Myocardial proteins are known to have a rapid turnover, and cardiac viability is dependent on the maintenance of the integrity of the protein synthetic mechanism. The studies of cardiac protein metabolism and the initial responses to hemodynamic overload, as well as to the common stresses as ischemia and ethanol exposure, will permit elucidation of the mechanisms of hypertrophy and potential therapeutic applications.
