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Dexamethasone-induced cardioprotection: A role for the phosphatase MKP-1?

2009; Elsevier BV; Volume: 84; Issue: 23-24 Linguagem: Inglês

10.1016/j.lfs.2009.03.014

1879-0631

Wenjun Fan, Sonia Genade, Amanda Genis, Barbara Huisamen, Amanda Lochner,

Chemotherapy-induced cardiotoxicity and mitigation

Previous studies suggested that p38 MAPK activation during sustained myocardial ischaemia and reperfusion was harmful. We hypothesize that attenuation of p38MAPK activity via dephosphorylation by the dual-specificity phosphatase MKP-1 should be protective against ischaemia/reperfusion injury. Since the glucocorticoid, dexamethasone, induces the expression of MKP-1, the aim of this study was to determine whether upregulation of this phosphatase by dexamethasone protects the heart against ischaemia/reperfusion injury.Male Wistar rats were treated with dexamethasone (3 mg/kg/day ip) for 10 days, before removal of the hearts for Western blot (ip Dex-P) or perfusion in the working mode (ip Dex+P). Hearts were subjected to 20 min global or 35 min regional ischaemia (36.5 degrees C) and 30 or 120 min reperfusion. In a separate series, dexamethasone (1 microM) was added to the perfusate for 10 min (Pre+Dex) before or after (Rep+Dex) ischaemia.Dexamethasone, administered intraperitoneally or added directly to the perfusate, significantly improved post-ischaemic functional recovery and reduced infarct size compared to untreated controls (p<0.05). These were associated with enhanced up-regulation of MKP-1 protein expression (arbitrary units (mean+/-SD): Untreated: 1; ip Dex-P: 2.59+/-0.22; ip Dex+P: 1.51+/-0.22; Pre+Dex: 4.11+/-0.73, Rep+15'Dex: 1.51+/-0.14; untreated vs. all groups, p<0.05) and attenuation of p38 MAPK activation (p<0.05) in all dexamethasone-treated groups, except for Rep+10'Dex. ERK and PKB/Akt activation were unchanged.Dexamethasone-induced cardioprotection was associated with upregulation of the phosphatase MKP-1 and inactivation of pro-apoptotic p38 MAPK.