Acute
myocardial infarction, the clinical manifestation of
ischemia-reperfusion (IR) injury, is a leading cause of death worldwide. Like ischemic preconditioning (IPC) induced by brief episodes of
ischemia and reperfusion,
ouabain preconditioning (OPC) mediated by Na/K-
ATPase signaling protects the heart against IR injury. Class I PI3K activation is required for IPC, but its role in OPC has not been investigated. While PI3K-IB is critical to IPC, studies have suggested that
ouabain signaling is PI3K-IA-specific. Hence, a pharmacological approach was used to test the hypothesis that OPC and IPC rely on distinct PI3K-I
isoforms. In Langendorff-perfused mouse hearts, OPC was initiated by 4 min of
ouabain 10 μM and IPC was triggered by 4 cycles of 5 min
ischemia and reperfusion prior to 40 min of global
ischemia and 30 min of reperfusion. Without affecting PI3K-IB,
ouabain doubled PI3K-IA activity and Akt phosphorylation at Ser(473). IPC and OPC significantly preserved cardiac contractile function and tissue viability as evidenced by left ventricular developed pressure and end-diastolic pressure recovery, reduced
lactate dehydrogenase release, and decreased
infarct size. OPC protection was blunted by the PI3K-IA inhibitor
PI-103, but not by the PI3K-IB inhibitor
AS-604850. In contrast, IPC-mediated protection was not affected by
PI-103 but was blocked by
AS-604850, suggesting that PI3K-IA activation is required for OPC while PI3K-IB activation is needed for IPC. Mechanistically, PI3K-IA activity is required for
ouabain-induced Akt activation but not PKCε translocation. However, in contrast to PKCε translocation which is critical to protection, Akt activity was not required for OPC. Further studies shall reveal the identity of the downstream targets of this new PI3K IA-dependent branch of OPC. These findings may be of clinical relevance in patients at risk for
myocardial infarction with underlying diseases and/or medication that could differentially affect the integrity of cardiac PI3K-IA and IB pathways.