Dexamethasone-induced cardioprotection: a role for the phosphatase MKP-1?
OBJECTIVE
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.


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 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.


RESULTS
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.


CONCLUSIONS
Dexamethasone-induced cardioprotection was associated with upregulation of the phosphatase MKP-1 and inactivation of pro-apoptotic p38 MAPK.
Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, South Africa.
W-J
WJ
Fan
S
S
Genade
A
A
Genis
B
B
Huisamen
A
A
Lochner
D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use*; D054638:Dual Specificity Phosphatase 1 / Q000502:physiology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar
D002316:Cardiotonic Agents; D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1