Key result
Inhibition of p38 MAPK with SB202190 during reperfusion significantly improved recovery of left ventricular work in rat hearts subjected to prolonged hypothermic ischemia (6.12 vs 1.96, p<0.05).
Absolute Event Rate: 6.12% vs 1.96%
p-value: p=<0.05
Inhibition of p38 MAPK during reperfusion significantly improves the recovery of mechanical function in isolated rat hearts subjected to prolonged hypothermic ischemia.
p38 MAPK inhibition may aid graft preservation in models; leaves open clinical translation pending human studies.
BACKGROUND: Mitogen-activated protein kinases (MAPKs), including extracellular-responsive kinase (ERK) and p38 MAPK, are activated by stresses associated with hypothermia-rewarming and ischemia-reperfusion. Their activation in heart is associated with beneficial (preconditioning) and adverse effects (apoptosis and impaired contractility). This study determined whether ERK and p38 MAPK activities are altered by hypothermic ischemia and normothermic reperfusion and the consequences of their inhibition on recovery of myocardial function. METHODS: Left ventricular work (L x min(-1) x mm Hg) was assessed during normothermic perfusion (30 min) of isolated rat hearts that were either freshly excised or previously subjected to hypothermic storage (8 hr, 3 degrees C) and rewarming (10 min, 37 degrees C) before normothermic reperfusion (30 min). Phospho-specific immunoblot analysis of p38 MAPK was performed in hearts and various cultured cells. RESULTS: Compared with fresh hearts, hearts subjected to hypothermia and rewarming demonstrated impaired left ventricular work (1.96+/-0.53, n=12 vs. 8.37+/-0.46, n=4, <0.05) during reperfusion. The ERK inhibitor, PD98059 (20 microM), present during storage and rewarming, caused modest improvement (3.66+/-0.75, n=9, <0.05). The p38 MAPK inhibitor, SB202190 (10 microM), when present during reperfusion, improved recovery (to 6.12+/-0.75, n=6, <0.05); it was ineffective if present only during rewarming (1.52+/-0.88, n=4). In rat2 fibroblasts, hypothermia and rewarming activated p38 MAPK and its downstream kinase MAPK-activated protein kinase 2, but not c-Jun N-terminal kinase/stress-activated protein kinase. CONCLUSIONS: Myocardial p38 MAPK and MAPK-activated protein kinase 2 are stimulated by hypothermia, ischemia, and rewarming and are detrimental to recovery of mechanical function of hearts subjected to prolonged hypothermic storage. Inhibition of p38 MAPK may be useful in protocols to improve the recovery of mechanical function of cold-stored hearts.
No takes yet. Share an insight, caveat, or question.
Clanachan et al. (2003) studied Hypothermic ischemia and normothermic reperfusion. ERK inhibitor (PD98059) and p38 MAPK inhibitor (SB202190) vs. Hearts subjected to hypothermia and rewarming without inhibitors was evaluated on Left ventricular work (L x min(-1) x mm Hg) (p=<0.05). Inhibition of p38 MAPK with SB202190 during reperfusion significantly improved recovery of left ventricular work in rat hearts subjected to prolonged hypothermic ischemia (6.12 vs 1.96, p<0.05).