Cardiac work is the major determinant of cardiac size. Conditions such as hypertension, aortic stenosis, and hyperthyroidism increase the work of the myocardium and lead to the development of hypertrophy. The rapid changes in cardiac RNA and protein synthesis that mediate this increase in cardiac growth have been well described. In contrast, cardiac atrophy, which can occur with decreased cardiac work, caloric deprivation, hypothyroidism and Addison's disease has not been well studied. The present studies are designed to characterize the changes in size, protein content, protein synthesis, RNA content and RNA synthesis in the novel model system of the transplanted heart. Heterotopic rat cardiac isografts are vasculary perfused organs that can maintain structural and functional integrity for prolonged periods of time. When placed in an infrarenal position the transplanted heart beats spontaneously but does essentially no external work. The myocardial response to the hemodynamic unloading associated with transplantation is a prompt decrease in muscle mass. To further characterize this atrophy response the rate of change of cardiac mass, total protein content, myosin content and myosin isoenzyme distribution will be measured. To probe the mechanism of decreased protein content, studies of in vivo and in vitro rates of total cardiac protein synthesis will be performed at various times after transplantation. The transplanted heart model allows the unique ability to simultaneously measure protein synthetic parameters in the in situ (working) heart and in the heterotopic (non-working) heart. To determine if changes in protein synthesis are a result of altered nucleic acid synthesis or content, RNA metabolism will be studied. At time points when protein synthesis in the transplanted heart is decreased, total RNA content, total RNA synthesis, total messenger RNA content and specific mRNA species including myosin mRNA will be measured and compared to the levels in the working heart. Since adult cardiac muscle, similar to the highly differentiated tissue of the central nervous system is unable to undergo cell division, it can only respond to stress or injury by changes in cell size and rates of protein synthesis. As a result of these studies we hope to be able to understand the basic mechanisms by which cardiac muscle responds to changes in workload and regulates its content of contractile proteins
Showing the most recent 10 out of 18 publications
