Grant: Project Grant

Enlargement and stiffening of the heart occurs when the heart is continuously exposed to conditions such as elevated blood pressure and/or increases in the amount of certain molecules, such as hormones, in the blood. Certain factors, including endothelin, also stimulate the heart to enlarge, or hypertrophy, by acting on cardiomyocytes - the muscle cells of the heart. In addition, fibroblasts, another type cell in the heart, become activated, increase in number, and make the walls of the heart stiffer and less able to relax. Relaxation of the heart with each heartbeat is essential for the heart to fill with blood for the next contraction. We are investigating how endothelin, a naturally occurring regulatory protein, is involved in fibroblast activation and cardiomyocyte enlargement. If the underlying cause for these processes (e.g., increased endothelin release, high blood pressure) continue to be present, a point is reached where the heart can no longer function properly. In this proposal, the means by which endothelin stimulates the cells (cardiomyocytes, fibroblasts) of the heart are being studied. There are many steps in the chain of events initiated by endothelin acting upon heart cells. The first step is the interaction of endothelin with specialized proteins, dedicated to binding endothelin, called receptors. The final results include changes in the growth and function of the heart. The cells of the heart contain two types of endothelin receptor. These receptors activate a network of signalling systems, similar to a telephone network, within the cell. In this project, the function of endothelin receptors that are located on the cell nucleus will be studied to determine their role in regulating the growth and function of muscle cells in the heart. The goal of this research it to identify novel targets for the development of drugs to be used to prevent or treat heart diseases.