p38 MAPK inhibition decreases TNF-alpha production and enhances postischemic human myocardial function

Introduction. TNF-alpha is a proinflammatory cytokine implicated in myocard ial dysfunction following ischemia/reperfusion (I/R). I/R results in myocar dial production of TNF-alpha and TNF-alpha suppresses myocardial contractil ity, p38 mitogen-activated protein kinase (MAPK) is a redox-sensitive prote in kinase involved in intracellular signaling leading to TNF-alpha producti on. It remains unknown if the human heart produces TNF-alpha after I/R and, if so, whether p38 MAPK is involved. Hypothesis. p38 MAPK inhibition enhances human myocardial post-IIR contract ile function by inhibition of myocardial TNF-alpha production. Methods. Human atrial trabeculae were suspended in organ baths, field simul ated at 1 Hz, and force development was recorded. Following a 90-min equili bration, trabeculae were exposed to a p38 MAPM inhibitor (SB 203580, 1 mu M ) or vehicle teach n = 6) prior to simulated ischemia (45 min hypoxia, subs trate-free, rapid pacing at 3 Hz) followed by 120 min reoxygenation. Myocar dial TNF-alpha levels were measured by ELISA at end reoxygenation. Results. I/R increased human myocardial TNF-alpha levels from 26.9 +/- 9.3 to 83.9 +/- 19.2 pg/g wet tissue (P < 0.05 perfusion vs I/R; ANOVA Bonferro ni/Dunn), while p38 MAPK inhibition decreased post-I/R myocardial TNF-alpha levels to 32.3 +/- 8.0 pg/g wet tissue (P > 0.05 p38 MAPK inhibition vs I/ R). p38 MAPK inhibition improved postischemic force development from 18.5 /- 2.1 to 37.0 +/- 2.0% baseline developed force (%BDF; P < 0.05 I/R vs p38 MAPK inhibition). Conclusions. (1) The human heart produces TNF-alpha after I/R, (2) p38 MAPK mediates myocardial I/R- induced TNF-alpha production, (3) p38 MAPK inhibi tion limits functional impairment after I/R, and (4) inhibition of ischemia -induced TNF-alpha production may represent a potent therapeutic strategy f or improving myocardial function after angioplasty, coronary bypass, or hea rt transplantation. (C) 1999 Academic Press.