Grant: Operating Grant

Background: The cardiac electricity-generating protein, named "HERG", is important for normal heart rhythm. A reduction in the amount of HERG protein disturbs heart rhythm and causes sudden death. Diseased conditions such as insufficient blood supply to the heart muscle (ischemic heart disease) is a common cause of irregular heartbeat and sudden death. Presently, it is not well understood how ischemic heart disease causes irregular heartbeat. Objectives: We aim to establish (1) that a special region of the HERG senses a reduced level of potassium in the blood to cause HERG to break down. (2) that this same region of HERG is easily broken down by biological molecules (named enzymes) released from heart cells as a result of insufficient blood supply. (3) a novel strategy using small synthetic molecules (peptides) to protect HERG and prevent sudden death in patients suffering from ischemic heart disease. Description of the research project: We have obtained evidence showing that a special region of HERG plays an important role in breaking down HERG in the heart when the blood potassium level is low or when blood supply to the heart muscle is insufficient. Ischemic heart disease increases the abundance of enzymes that selectively break down HERG. We will study which enzymes released from heart cells break down HERG. We will use cultured cells as well as heart cells from rats and rabbits. We will also make a rabbit model that mimics human ischemic heart disease. Importantly, we will design synthetic HERG-binding molecules to shield the special region and thereby protect HERG against breakdown. Significance: Ischemic heart disease is the leading disease in our society, and it causes irregular heartbeat and sudden death. The proposed research can potentially lead to novel drugs for treating irregular heartbeat and preventing sudden death in patients with ischemic heart disease.