Tumor necrosis factor-induced protection of the murine heart is independent of p38-MAPK activation.

Abstract

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.

• Authors: Masaya Tanno, Diana A Gorog, Mohamed Bellahcene, Xuebin Cao, Roy A Quinlan, Michael S Marber
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 35 Issue 12 Pg. 1523-7 (Dec 2003) ISSN: 0022-2828 [Print] England
• PMID: 14654378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Pyridines
• Tumor Necrosis Factor-alpha
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 203580

Topics

• Animals
• Blotting, Western
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Imidazoles (pharmacology)
• Ischemic Preconditioning, Myocardial
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Myocardial Infarction (drug therapy, etiology, pathology)
• Myocardial Ischemia (metabolism, pathology)
• Myocardial Reperfusion
• Myocardium (enzymology)
• Phosphorylation
• Pyridines (pharmacology)
• Time Factors
• Tumor Necrosis Factor-alpha (pharmacology, therapeutic use)
• p38 Mitogen-Activated Protein Kinases