Reduction of infarct size with D-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial K(ATP) channels.
Prophylactic treatment with D-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 underlying D-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 K(ATP) channels) in the infarct-sparing effect of D-myo-Ins(1,4,5)P3. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated with D-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+ (K(ATP)) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in both D-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, K(ATP) channels. Moreover, the benefits of D-myo-Ins(1,4,5)P3 were 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)P3 evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective epsilon-isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial K(ATP) channels participate in the reduction of infarct size afforded by prophylactic administration of D-myo-Ins(1,4,5)P3.
Przyklenk
Karin
K
Dept. of Emergency Medicine, Univ. of Massachusetts Medical School, 55 Lake Ave. N, Worcester, MA 01655, USA. Karin.Przyklenk@umassmed.edu
Maynard
Michelle
M
Whittaker
Peter
P
D000470:Alkaloids; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D053119:Benzophenanthridines; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D008929:Mitochondria, Heart / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D011817:Rabbits; D013237:Stereoisomerism
D000470:Alkaloids; D001549:Benzamides; D053119:Benzophenanthridines; D002316:Cardiotonic Agents; D002867:Chromones; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D009025:Morpholines; D010617:Phenanthridines; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C052853:5-hydroxydecanoic acid; D015544:Inositol 1,4,5-Trisphosphate; C410297:HMR 1098; C016299:chelerythrine; D019869:Phosphatidylinositol 3-Kinases; D051744:Protein Kinase C-epsilon