Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning. (March 2015)

• Record Type: Journal Article
• Authors: Duan, Qiming; Madan, Namrata D.; Wu, Jian; Kalisz, Jennifer; Doshi, Krunal Y.; Haldar, Saptarsi M.; Liu, Lijun; Pierre, Sandrine V.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 80(2015:Mar.)
• Page Start: 114
• Page End: 125
• Publication Date: 2015-03
• Subjects: Preconditioning -- PI3K -- Ischemia–reperfusion injury -- Na/K-ATPase; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2014.12.021
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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. Highlights: Inhibition of PI3K-IA but not PI3K-IB blocked ouabain preconditioning (OPC). Inhibition of PI3K-IB but not PI3K-IA blocked ischemic preconditioning (IPC). Pre-ischemic inhibition of Akt inhibited IPC but not OPC. Ouabain induced PKCε activation was not altered by PI3K inhibition. PKCε translocation is necessary but not sufficient for OPC.