title: Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C.
abstract: The present study is designed to test whether phosphatidylinositol 3-kinase (PI3-kinase) has a role in the signaling pathway in ischemic preconditioning (PC) and whether it is proximal or distal to protein kinase C (PKC). Before 20 minutes of global ischemia, Langendorff-perfused rat hearts were perfused for 20 minutes (control); preconditioned with 4 cycles of 5-minute ischemia and 5-minute reflow (PC); treated with either wortmannin (WM) or LY 294002 (LY), each of which is a PI3-kinase inhibitor, for 5 minutes before and throughout PC; treated with 1,2-dioctanoyl-sn-glycerol (DOG), an activator of PKC for 10 minutes (DOG); treated identically to the DOG group except with WM added 10 minutes before and during perfusion with DOG; or treated with either WM or LY for 25 minutes. Recovery of left ventricular developed pressure (LVDP; percentage of initial preischemic LVDP), measured after 30 minutes of reflow, was improved by PC (72+/-2% versus 36+/-4% in control; P<0.001), and this was blocked by WM and LY (41+/-4% and 43+/-5%, respectively; P<0.05 compared with PC). DOG addition improved postischemic LVDP (67+/-6%; P<0.001 compared with control), but in contrast to its effect on PC, WM did not completely eliminate the protective effect of DOG (52+/-4%; P>0.05 compared with DOG; P<0.05 compared with control). PC induced phosphorylation of protein kinase B and translocation of PKC epsilon, and it increased NO production, and these effects were blocked by WM, which suggests a role for PI3-kinase in PC upstream of PKC and NO.
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. tong@niehs.nih.gov
authors.forename: H
authors.initials: H
authors.lastname: Tong
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Steenbergen
authors.forename: E
authors.initials: E
authors.lastname: Murphy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004075:Diglycerides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D019194:Ischemic Preconditioning; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D000077191:Wortmannin
chemical_list: D000255:Adenosine Triphosphate; D000730:Androstadienes; D002867:Chromones; D004075:Diglycerides; D004791:Enzyme Inhibitors; D006003:Glycogen; D007527:Isoenzymes; D009025:Morpholines; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D010726:Phosphodiesterase Inhibitors; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C044295:1,2-dioctanoylglycerol; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C497257:Prkce protein, rat