Tumor necrosis factor-induced protection of the murine heart is independent of p38-MAPK activation.
Brief exposure to tumor necrosis factor (TNF) is known to trigger subsequent cardioprotection. TNF activates multiple downstream signaling cascades including p38-MAPK, a kinase known to initiate ischemic preconditioning. However, it is not known whether this kinase is similarly involved in TNF-induced cardioprotection. In isolated perfused murine hearts, subjected to 30-min global ischemia/2-h reperfusion, infarction/risk volume was significantly reduced by pretreatment with TNF for 15 min at 0.5 ng/ml, but not at 5 or 10 ng/ml, followed by 10-min washout vs. control (% I/R = 31 +/- 3, 46 +/- 5 or 54 +/- 3 vs. 48 +/- 5; P = 0.01, 0.80 and 0.25, respectively). This was in direct contrast to the concentration dependence of myocardial p38-MAPK phosphorylation, as measured by dual phosphorylated p38-MAPK, which was apparent at TNF concentrations of 5 and 10 ng/ml but not at 0.5 ng/ml vs. time-matched control (as % basal 315 +/- 25, 422 +/- 94 and 97 +/- 25 vs. 95 +/- 10; P < 0.01, 0.01 and =0.86, respectively). However, phosphorylation of p38-MAPK at 10 min of ischemia was similar among groups (as % basal 393 +/- 98, 410 +/- 67 and 369 +/- 49 for time-matched control, 0.5 and 5 ng/ml, respectively). These patterns were also reflected in the phosphorylation of the downstream substrate HSP27. Furthermore, the effects of TNF on infarct size were not affected by SB203580 (1 micromol/l). These findings suggest that the pre-ischemic activation of p38-MAPK by TNF does not contribute to cardioprotection afforded by this agent.
Tanno
Masaya
M
The Rayne Institute, Department of Cardiology, King's College London, St. Thomas' Hospital Lambeth Palace Road, London SEI 7EH, UK.
Gorog
Diana A
DA
Bellahcene
Mohamed
M
Cao
Xuebin
X
Quinlan
Roy A
RA
Marber
Michael S
MS
D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580