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: H Tong, W Chen, C Steenbergen, E Murphy
• Journal: Circulation research (Circ Res) Vol. 87 Issue 4 Pg. 309-15 (Aug 18 2000) ISSN: 0009-7330 [Print] United States
• PMID: 10948065 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androstadienes
• Chromones
• Diglycerides
• Enzyme Inhibitors
• Isoenzymes
• Morpholines
• Phosphodiesterase Inhibitors
• Proto-Oncogene Proteins
• 1,2-dioctanoylglycerol
• Nitric Oxide
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Adenosine Triphosphate
• Glycogen
• Prkce protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Protein Kinase C
• Protein Kinase C-epsilon
• Wortmannin

Topics

• Adenosine Triphosphate (metabolism)
• Androstadienes (pharmacology)
• Animals
• Chromones (pharmacology)
• Coronary Circulation (drug effects, physiology)
• Diglycerides (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Glycogen (metabolism)
• Hydrogen-Ion Concentration
• Ischemic Preconditioning
• Isoenzymes (metabolism)
• Male
• Morpholines (pharmacology)
• Myocardial Reperfusion Injury (metabolism)
• Myocardium (enzymology)
• Nitric Oxide (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphodiesterase Inhibitors (pharmacology)
• Phosphorylation
• Protein Kinase C (metabolism)
• Protein Kinase C-epsilon
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Rats
• Rats, Sprague-Dawley
• Recovery of Function (drug effects, physiology)
• Wortmannin