Hypoxia and Ischemia Signaling

Ischemia denotes a medical condition of locally decreased blood perfusion due to mechanical obstruction of the blood supply. In the myocardium, sudden onset of coronary artery occlusion causes myocardial ischemia and subsequently infarction. Deficiency of the blood supply results in tissue hypoxia in addition to nutrient deprivation. Hypoxia promotes anaerobic metabolism and generation of reactive oxygen species (ROS). While reperfusion is essential for salvaging the hypo-perfused area, restoration of blood flow produces additional ROS. High concentrations of ROS can cause cell death, whereas low to mild levels of ROS trigger a cascade of signaling events. The amount of cell death reflects the severity of the infarct, as high levels of cell death can lead to heart failure and even fatality. In experimental models of myocardial ischemia, pre- and post-conditioning by short pulses of ischemia can preserve cardiac function and reduce the quantity of cells that die from prolonged ischemia. Intracellular levels of adenosine increase during pre- and post-conditioning due to degradation of nucleotides. Extracellular adenosine binds to its receptors on the plasma membrane and initiates G-protein mediated signaling, leading to activation of phosphoinositide 3-kinase (PI3K), protein kinase C (PKC) and Mitogen Activated Protein Kinases (MAPKs), thereby contributing to vasodilation and cardiac protection. ROS produced during ischemia or ischemic reperfusion initiate a cascade of signaling events, from G-protein activation and increases in intracellular calcium, to activation of PI3K, PKC and MAPKs. This chapter describes the details of these signaling events and their impact on biological end points such as vasodilation, adaptation, apoptosis and hypertrophy.