Ban Kiwon, Cooper Andrew J, Samuel Sara, Bhatti Adil, Patel Mikin, Izumo Seigo, Penninger Josef M, Backx Peter H, Oudit Gavin Y, Tsushima Robert G
Department of Medicine and Physiology, University of Toronto, Ontario, Canada.
Circ Res. 2008 Sep 12;103(6):643-53. doi: 10.1161/CIRCRESAHA.108.175018. Epub 2008 Aug 7.
Ischemic preconditioning (IPC) is a potent cellular protective mechanism whereby brief periods of sublethal ischemia protect the myocardium from prolonged ischemia-induced injury. We demonstrate the selective role of phosphatidylinositol 3-kinase (PI3K) isoforms in IPC. Hearts from PI3Kgamma knockout mice (PI3Kgamma(-/-)) displayed poorer functional recovery and greater tissue injury following IPC compared to wild-type and PI3Kgamma(+/-) hearts. Examination of the cell-signaling pathways revealed restored phosphorylation levels of Akt and glycogen synthase kinase (GSK)3beta in wild-type hearts, which were abolished in PI3Kgamma(-/-) hearts subjected to IPC. Inhibition of GSK3beta by LiCl reversed the loss in protection in PI3Kgamma(-/-) hearts. In contrast, mice expressing a cardiac-specific kinase-deleted PI3Kalpha (PI3KalphaDN) were resistant to injury induced by 30 minutes of ischemia followed by 40 minutes of reperfusion. Furthermore, the resistance of PI3KalphaDN hearts to ischemia/reperfusion correlated with the persistent expression of p110gamma and was blocked by the PI3K inhibitor wortmannin, suggesting the possible enhanced cell signaling through the PI3Kgamma pathway. These results demonstrate the importance of the PI3Kgamma-Akt-GSK3beta signaling pathway in IPC. Selective activation of myocardial PI3Kgamma may be an attractive target for the treatment of ischemic heart disease.
缺血预处理（IPC）是一种强大的细胞保护机制，即短暂的亚致死性缺血可保护心肌免受长时间缺血诱导的损伤。我们证明了磷脂酰肌醇3激酶（PI3K）亚型在缺血预处理中的选择性作用。与野生型和PI3Kγ（+/-）心脏相比，PI3Kγ基因敲除小鼠（PI3Kγ（-/-））的心脏在缺血预处理后功能恢复较差，组织损伤更严重。对细胞信号通路的检测显示，野生型心脏中Akt和糖原合酶激酶（GSK）3β的磷酸化水平恢复，而在接受缺血预处理的PI3Kγ（-/-）心脏中则被消除。用氯化锂抑制GSK3β可逆转PI3Kγ（-/-）心脏中保护作用的丧失。相反，表达心脏特异性激酶缺失的PI3Kα（PI3KαDN）的小鼠对30分钟缺血后再灌注40分钟诱导的损伤具有抗性。此外，PI3KαDN心脏对缺血/再灌注的抗性与p110γ的持续表达相关，并被PI3K抑制剂渥曼青霉素阻断，这表明可能通过PI3Kγ途径增强细胞信号传导。这些结果证明了PI3Kγ-Akt-GSK3β信号通路在缺血预处理中的重要性。选择性激活心肌PI3Kγ可能是治疗缺血性心脏病的一个有吸引力的靶点。
