Reduction of infarct size with D-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial K(ATP) channels.
Reduction of infarct size with D-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial K(ATP) channels.
复制标题
D-肌醇三磷酸减少梗塞面积：PI3 激酶和线粒体 K(ATP) 通道的作用。
DOI：
10.1152/ajpheart.00799.2005
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Whittaker,Peter
中科院分区：
文献类型：
--
作者：
Przyklenk,Karin;Maynard,Michelle;Whittaker,Peter
Prophylactic treatment withd-myo-inositol 1,4,5-trisphosphate hexasodium [d-myo-Ins(1,4,5)P3], the sodium salt of the endogenous second messenger Ins(1,4,5)P3, triggers a reduction of infarct size comparable in magnitude to that seen with ischemic preconditioning (PC). However, the mechanisms underlyingd-myo-Ins(1,4,5)P3-induced protection are unknown. Accordingly, our aim was to investigate the role of four archetypal mediators implicated in PC and other cardioprotective strategies (i.e., PKC, PI3-kinase/Akt, and mitochondrial and/or sarcolemmal KATPchannels) in the infarct-sparing effect ofd-myo-Ins(1,4,5)P3. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated withd-myo-Ins(1,4,5)P3, 5 treated with PC, and 5 control cohorts] underwent 30 min of coronary artery occlusion and 2 h of reflow. One set of control,d-myo-Ins(1,4,5)P3, and PC groups received no additional treatment, whereas the remaining sets were infused with chelerythrine, LY-294002, 5-hydroxydecanoate (5-HD), or HMR-1098 [inhibitors of PKC, PI3-kinase, and mitochondrial and sarcolemmal ATP-sensitive K+(KATP) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in bothd-myo-Ins(1,4,5)P3- and PC-treated hearts versus controls.d-myo-Ins(1,4,5)P3-induced cardioprotection was blocked by 5-HD but not HMR-1098, thereby implicating the involvement of mitochondrial, but not sarcolemmal, KATPchannels. Moreover, the benefits ofd-myo-Ins(1,4,5)P3were abrogated by LY-294002, whereas, in contrast, chelerythrine had no effect. These latter pharmacological data were corroborated by immunoblotting:d-myo-Ins(1,4,5)P3evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective ε-isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial KATPchannels participate in the reduction of infarct size afforded by prophylactic administration ofd-myo-Ins(1,4,5)P3.
