Ischemic Injury
Ischemic injury and ischemia induced tissue damage are the result of deficient blood supply to tissues due to obstruction of arterial inflow reaching tissues and cells in the affected area, and causing oxidative stress. Oxidative stress results from imbalance between the amount of oxidants produced and antioxidants, leading to tissue injury depending on the severity and duration. Reactive oxygen species (ROS) are produced physiologically during respiration by the mitochondrial electron transport chain, and pathologically by neutrophils and phagocytes involved in inflammation and infection. In the heart, after ischemia-reperfusion (I/R) or doxorubicin exposure, ROS production is increased. ROS plays a major role in myocyte injury through protein oxidation, lipid peroxidation, nitrosylation, and DNA oxidation and mutagenesis. During reperfusion, ROS can trigger mitochondrial permeability transition pore (mPTP) opening, leading to irreversible cell death. In addition, ROS-induced ROS release has been proposed as the mechanism underlying the wave of mPTP opening in myocytes (42).
TRPM2
Transient Receptor Potential Melastatin 2 (TRPM2) ion channel has an essential function in maintaining cell survival following oxidant injury. However, the mechanisms by which TRPM2 channels enhance mitochondrial bioenergetics and protect against oxidative stress induced cardiac injury are still be explored. Our lab is research these mechanisms in order to form a better understanding of these injuries and potentially elicit ways to reduce their severity or prevent them altogether.
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TRPM2 in Ischemic Injury and Oxidative Stress
Transient Receptor Potential Melastatin 2 (TRPM2) ion channel plays an essential role in maintaining cell survival following oxidant injury, but the mechanisms by which they do so remain unclear. Our studies have explored the role of proline-rich tyrosine kinase 2 (Pyk2) in TRPM2 signaling, noting that activation of TRPM2 led to increases in Pyk2 phosphorylation in mice. Overall our studies indicate that Ca2+ influx from activated TRPM2 channels phosphorylates Pyk2, which in turn likely leads to augmented mitochondrial Ca2+ uptake and thus enhanced ATP generation. When this phosphorylated Pyk2 translocates to mitochondria the result is better mitochondrial bioenergetics for maintaining cardiac health. After ischemic injury Pyk2 activates pro-survival signaling molecules and prevents excessive increases in reactive oxygen species, thereby affording protection from ischemia/reperfusion injuries.