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

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

doi:10.1016/j.lfs.2009.03.014

Cited by 25 publications

(24 citation statements)

References 55 publications

(59 reference statements)

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“…Indeed, Fan and co-workers have demonstrated that dexamethasone, administered intraperitoneally or added directly to the perfusate, significantly improved post-ischemic functional recovery and reduced infarct size compared to untreated controls [94]. These were associated with associated with upregulation of MKP-1 protein expression [94]. Furthermore, it was also shown by us that upregulation of MKP-1 during simulated ischemia/reperfusion is associated with an attenuation of apoptosis in neonatal cardiomyocytes [93].…”

Section: Map Kinase Phosphatase-1 (Mkp-1): a Mediator Of The Beneficimentioning

confidence: 78%

“…The inhibition of p38-MAPK was then shown to be mediated by MKP-1. We and others have also demonstrated that dexamethasone induces the expression of MKP-1 which potently inactivated p38-MAPK [93][94]. Wu and Bennet (2005) demonstrated that MKP-1 promotes cell survival in fibroblasts through the attenuation of stress responsive MAPK-mediated apoptosis [95].…”

Section: Map Kinase Phosphatase-1 (Mkp-1): a Mediator Of The Beneficimentioning

confidence: 79%

“…MAPKs are activated during ischemia/reperfusion-induced stress in the heart. It was also demonstrated that glucocorticoids act via MKP-1 induction and subsequent p38-MAPK inhibition to induce cardioprotection during ischemia/reperfusion-induced stress [94].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that upregulation of MKP-1 during ischemia/reperfusion-induced stress attenuates myocardial injury [93,94]. MKP-1, found predominantly in the nucleus, is a dual specific phosphatase which dephosphorylates phosphotyrosine and phosphothreonine-containing protein kinases such as the MAPKs.…”

Section: Discussionmentioning

confidence: 99%

“…In view of the significant contribution of apoptosis, necrosis and autophagy during ischemia/reperfusion-induced stress, it is expected that GC-induced cardioprotection to be associated with reduced apoptosis and necrosis. Indeed, Fan and co-workers have demonstrated that dexamethasone, administered intraperitoneally or added directly to the perfusate, significantly improved post-ischemic functional recovery and reduced infarct size compared to untreated controls [94]. These were associated with associated with upregulation of MKP-1 protein expression [94].…”

Section: Map Kinase Phosphatase-1 (Mkp-1): a Mediator Of The Beneficimentioning

confidence: 99%

See 4 more Smart Citations

Glucocorticoid-Induced Cardioprotection: A Novel Role for Autophagy

Engelbrecht¹,

Loos²

2012

Glucocorticoids - New Recognition of Our Familiar Friend

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Section: Map Kinase Phosphatase-1 (Mkp-1): a Mediator Of The Beneficimentioning

confidence: 78%

Section: Map Kinase Phosphatase-1 (Mkp-1): a Mediator Of The Beneficimentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Map Kinase Phosphatase-1 (Mkp-1): a Mediator Of The Beneficimentioning

confidence: 99%

See 3 more Smart Citations

Glucocorticoid-Induced Cardioprotection: A Novel Role for Autophagy

Engelbrecht¹,

Loos²

2012

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Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity

Zheng

Zhang

et al. 2019

Arch Toxicol

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Kinases and phosphatases in ischaemic preconditioning: a re-evaluation

et al. 2010

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Activation of several protein kinases occurs during myocardial ischaemia and during subsequent reperfusion. In contrast to the intensive investigation into the significance of kinase activation in cardioprotection, relatively little is known about the role of the phosphatases in this regard. The aim of this study was to re-evaluate the putative roles of PP1 and PP2A in ischaemia/reperfusion and in triggering ischaemic preconditioning. Isolated perfused working rat hearts were subjected to sustained global (15 or 20 min) or regional ischaemia (35 min), followed by reperfusion. Hearts were preconditioned using global ischaemia (1 x 5 or 3 x 5 min, alternated with 5 min reperfusion). To inhibit both PP1 and PP2A cantharidin (5 muM) was used. To inhibit PP2A only, okadaic acid (7.5 nM) was used. The drugs were administered during the preconditioning protocol, before onset of sustained ischaemia (pretreatment) or during reperfusion. Endpoints were mechanical recovery during reperfusion, infarct size and activation of PKB/Akt, p38 MAPK and ERK p42/p44, as determined by Western blot. Pretreatment of hearts with okadaic acid or cantharidin caused a significant reduction in mechanical recovery after 15 or 20 min global ischaemia. Administration of the drugs during an ischaemic preconditioning protocol abolished functional recovery during reperfusion and significantly increased infarct size. Administration of the drugs during reperfusion had no deleterious effects and increased functional recovery in 3 x PC hearts. To find an explanation for the differential effects of the inhibitors depending on the time of administration, hearts were freeze-clamped at different time points during the perfusion protocol. Administration of cantharidin before 5 min ischaemia activated all kinases. Subsequent reperfusion for 5 min without the drug maintained activation of the kinases until the onset of sustained ischaemia. Cantharidin given during preconditioning was associated with activation of p38MAPK and PKB/Akt during reperfusion after sustained ischaemia. However, administration of the drug during reperfusion only after sustained ischaemia caused activation of both PKB/Akt and ERK p42/p44. Phosphatase inhibition immediately prior to the onset of sustained ischaemia or during preconditioning abolishes protection during reperfusion, while inhibition of these enzymes during reperfusion either had no effect or enhanced the cardioprotective effects of preconditioning. It is proposed that inhibition of phosphatases during reperfusion may prolong the period of RISK activation and hence protect the heart.

show abstract

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

Cited by 25 publications

References 55 publications

Glucocorticoid-Induced Cardioprotection: A Novel Role for Autophagy

Glucocorticoid-Induced Cardioprotection: A Novel Role for Autophagy

Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity

Kinases and phosphatases in ischaemic preconditioning: a re-evaluation

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