The present proposal has 3 objectives. The first concerns the restoration or preservation of myocardial protein synthesis with reperfusion following ischemia; the second, the regulation of cardiac growth and atrophy with the model of heterotopically transplanted cardiac isografts; and the third, the effect of chronic ethanol ingestion on synthesis of proteins in intracellular fractions and organelles. (1) Severe oxygen deprivation inhibits protein synthesis and ultimately leads to death of the myocyte. Current therapy involves rapid reperfusion in order to maintain the cell viability. This reperfusion may accelerate cell damage with protein denaturation, and maintenance of normal protein synthesis to replace damaged and denatured proteins is essential to assure life of the myocyte. The present proposal will study inhibition of protein synthesis i ischemia in different cellular constituents and evaluate methods to restore or preserve protein synthesis during reperfusion with agents as free radical scavengers, polyamines and stimulants of protein synthesis. The ultimate purpose is to allow replacement of the denatured proteins and restoration of damaged organelles so that the viability of the heart pump is maintained. (2) Increased workloads induce cardiac growth by increasing protein synthesis, but the regulatory mechanism is still unclear. It has been shown that following transplantation, the young donor heart survives, shows a decrease in protein synthesis and actually decreases in size. The proposal will study steps necessary to overcome the regression of synthesis and to evaluate the thesis that a workload is essential for normal cardiac growth in the young animal. (3) One of the causes of alcoholic cardiomyopathy may be defective protein synthesis which has been demonstrated in several laboratories. One of the inhibited proteins is actin. Since ultrastructural changes in various organelles may be seen in the end stages of the cardiomyopathy, it is the purpose of the study to examine protein synthesis in various organelles after prolonged ethanol ingestion in the growing animal and to attempt to overcome the inhibition wit agents as polyamines. The latter have already been shown to overcome ethanol inhibition of hepatic albumin synthesis.
