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

Aims: 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. Main methods: 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 °C) and 30 or 120 min reperfusion. In a separate series, dexamethasone (1 μM) was added to the perfusate for 10 min (Pre + Dex) before or after (Rep + Dex) ischaemia. Key findings: 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. Significance: Dexamethasone-induced cardioprotection was associated with upregulation of the phosphatase MKP-1 and inactivation of pro-apoptotic p38 MAPK. © 2009 Elsevier Inc. All rights reserved.