Grant: Project Grant

Heart disease is the leading cause of death in Canada with many patients going on to develop heart failure. Rising numbers of diabetes patients contributes to this trend. It is increasingly recognized that the early life environment (e.g. gestational diabetes) has a significant influence on the risk of diabetes and heart disease in the children. Gestational diabetes occurs during pregnancy when the mother is unable to control her blood sugar levels. A better understanding of the complex interplay between early life and heart disease is essential for the earlier and better treatment of its root causes. Current medications only minimize the symptoms of heart failure. Failing hearts are like an engine running out of fuel because the heart does not pump enough blood to meet the requirements of the body. Two factors contribute to heart failure development. One is the inability of the heart to produce enough energy to pump blood to the rest of the body. A second is high levels of reactive oxygen species (ROS), which are by-products of oxygen that damage heart tissue, interfering with its ability to pump blood. Mitochondria produce energy for the cell and are also the major site of damaging ROS production. We found that in the offspring of mothers with gestational diabetes the heart mitochondria were dysfunctional and when these offspring were older they developed heart failure. We will target the mitochondria in the heart to optimize energy production and reduce levels of ROS to stop heart failure. SIRT3 is an interesting cellular protein because it also increases energy production and reduces ROS in cells. Thus, activation of SIRT3 could supply more fuel to the engine of the heart and prevent damage by ROS to the heart that will allow it to pump blood better. This work aims to answer fundamental questions about the disease processes involved in heart failure and whether increasing cardiac energy production and reducing ROS levels are a viable treatment of heart failure.