Abstract 399: Reactive Oxygen Species in Myocardial Ischemic Injury and Protection
Myocardial injury following ischemia/reperfusion (I/R) is a common clinical scenario in patients suffering from ischemic heart disease. An excessive production of reactive oxygen species (ROS) during the early phase of reperfusion following myocardial ischemia has been proposed to contribute to reperfusion injury. Paradoxically, the ROS has also been recognized as a trigger of pro-survival signaling pathways mediating cardioprotection at a low level. However, the precise mechanisms for the dual role of ROS have not yet been fully clarified. To address this question, using intermittent hypobaric hypoxia (IHH) as a cardioprotective model, combining with H2O2 pre- and post-conditioning, we studied the level and roles of ROS during early reperfusion following ischemia in I/R injury and protection and explored the regulatory mechanisms underlying. Our results reveal that the elevated ROS generated during early reperfusion are injurious but insufficient to reach the threshold to trigger protective signaling pathways. The moderate level of ROS, higher than that elevated by I/R, during early reperfusion is critical for triggering cardioprotection against I/R injury via alleviating intracellular Ca2+ overload and preserving mitochondrial function through the efficient activation of Akt, PKCε[[Unable to Display Character: ]]and JAK2/STAT3 pathways. We then identified the downstream target of ROS-JAK2/STAT3 signals that interacts with the sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2) to improve the activation of SERCA2 and subsequently regulate intracellular Ca2+ homeostasis. When the heart is exposed to excessive ROS, the activation of protective mechanisms reaches a plateau and fails to counteract the severe nonspecific oxidative stress. These findings provide a new angle to interpret the controversial roles of ROS in myocardial I/R and demonstrate that the differential effects of ROS in myocardial I/R are derived from a quantity-dependent wrestling between its detrimental and signaling roles.
Author Disclosures: H. Yang: None. J. Tan: None. J. Liu: None. L. Wu: None. Z. Wang: None.
- © 2015 by American Heart Association, Inc.