Role of p38 MAPK in ischemia/reperfusion-induced gastric injury in mice

Although acute adenosine preconditioning (PC) is well established, the signaling pathways mediating this cardioprotection remain unclear. Because adenosine receptor agonists activate p38 MAPK and this kinase has been implicated in ischemic and pharmacological PC, the purpose of this study was to determine the role of p38 MAPK in acute adenosine receptor PC. The role of p38 MAPK activation in discrete subcellular compartments during ischemia-reperfusion was also determined. The following groups were used in an in vivo rat ischemia-reperfusion model: 1) control (10% DMSO iv), 2) the A1/A2a adenosine receptor AMP-579 (50 μg/kg iv), 3) AMP-579 + the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 μg/kg iv), 4) AMP-579 + the p38 MAPK inhibitor SB-203580 (1 mg/kg iv), and 5) SB-203580 alone. p38 MAPK activation was measured by Western blot analysis in cytosolic, mitochondrial, membrane, and nuclear/myofilament fractions obtained from hearts at preischemic, ischemic, and reperfusion time points. A significant reduction in infarct size was observed with AMP-579 PC, an effect blocked by DPCPX or SB-203580 pretreatment. AMP-579 treatment was associated with a significant increase in p38 MAPK activation in the nuclear/myofilament fraction before ischemia, whereas no activation of this kinase occurred during ischemia or reperfusion. In contrast, p38 MAPK was activated in the mitochondrial fraction by ischemia and in the cytosolic, mitochondrial, and membrane fractions by reperfusion in the control group. SB-203580 blocked the AMP-579-induced increase in phosphorylation of the downstream p38 substrate activating transcription factor-2. These results suggest a role for p38 MAPK activation in discrete subcellular compartments in acute adenosine A1 receptor PC.

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Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation

Journal of Transplantation ◽

10.1155/2012/928954 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 30

Author(s):

Giuseppe Vassalli ◽

Giuseppina Milano ◽

Tiziano Moccetti

Keyword(s):

Heart Transplantation ◽

Organ Transplantation ◽

P38 Mapk ◽

Cold Storage ◽

Organ Procurement ◽

Ischemia Reperfusion ◽

Solid Organ ◽

Mapk Activation ◽

Mitogen Activated Protein

In solid organ transplantation, ischemia/reperfusion (IR) injury during organ procurement, storage and reperfusion is an unavoidable detrimental event for the graft, as it amplifies graft inflammation and rejection. Intracellular mitogen-activated protein kinase (MAPK) signaling pathways regulate inflammation and cell survival during IR injury. The four best-characterized MAPK subfamilies are the c-Jun NH2-terminal kinase (JNK), extracellular signal- regulated kinase-1/2 (ERK1/2), p38 MAPK, and big MAPK-1 (BMK1/ERK5). Here, we review the role of MAPK activation during myocardial IR injury as it occurs during heart transplantation. Most of our current knowledge regarding MAPK activation and cardioprotection comes from studies of preconditioning and postconditioning in nontransplanted hearts. JNK and p38 MAPK activation contributes to myocardial IR injury after prolonged hypothermic storage. p38 MAPK inhibition improves cardiac function after cold storage, rewarming and reperfusion. Small-molecule p38 MAPK inhibitors have been tested clinically in patients with chronic inflammatory diseases, but not in transplanted patients, so far. Organ transplantation offers the opportunity of starting a preconditioning treatment before organ procurement or during cold storage, thus modulating early events in IR injury. Future studies will need to evaluate combined strategies including p38 MAPK and/or JNK inhibition, ERK1/2 activation, pre- or postconditioning protocols, new storage solutions, and gentle reperfusion.

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Role of p38 MAPK signaling in lung injury following intestinal ischemia/reperfusion in mice

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2010.00254 ◽

2010 ◽

Vol 30 (3) ◽

pp. 254-257

Author(s):

De-yi ZHENG ◽

Jian-ming WANG ◽

Yi-tao JIA ◽

Jin-feng FU ◽

Kai-yang LU ◽

...

Keyword(s):

Lung Injury ◽

P38 Mapk ◽

Intestinal Ischemia ◽

Ischemia Reperfusion ◽

Mapk Signaling ◽

Intestinal Ischemia Reperfusion

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Differential Activation of Mitogen-activated Protein Kinases in Ischemic and Anesthetic Preconditioning

Anesthesiology ◽

10.1097/00000542-200401000-00013 ◽

2004 ◽

Vol 100 (1) ◽

pp. 59-69 ◽

Cited By ~ 54

Author(s):

Rafaela da Silva ◽

Thomas Grampp ◽

Thomas Pasch ◽

Marcus C. Schaub ◽

Michael Zaugg

Keyword(s):

Protein Kinases ◽

P38 Mapk ◽

Functional Recovery ◽

Ischemia Reperfusion ◽

Protective Effects ◽

Mitogen Activated Protein Kinases ◽

Mapk Activity ◽

Anesthetic Preconditioning ◽

Mitogen Activated Protein

Background Accumulating evidence pinpoints to the pivotal role of mitogen-activated protein kinases (MAPKs) in the signal transduction underlying cardiac preconditioning. Methods PD98059, an inhibitor of extracellular signal-regulated protein kinase (MEK-ERK1/2), and SB203580, an inhibitor of p38 MAPK, were used to evaluate the role of MAPKs with respect to postischemic functional recovery in isolated perfused rat hearts subjected to ischemic preconditioning (IPC) and anesthetic preconditioning (APC). Western blot analyses were used to determine the degree of ERK1/2 and p38 MAPK activation after the application of the preconditioning stimulus and after ischemia-reperfusion. Immunohistochemical staining served to visualize subcellular localization of activated MAPKs. Results PD98059 and SB203580 abolished postischemic functional recovery in IPC but not in APC. IPC but not APC markedly activated ERK1/2 and p38 MAPK, which were abrogated by coadministration of the specific blockers. Conversely, IPC and APC enhanced ERK1/2 activity after ischemia-reperfusion as compared to nonpreconditioned hearts, and IPC in addition enhanced p38 MAPK activity. Coadministration of PD98059 and SB203580 during IPC but not during APC inhibited postischemically enhanced MAPK activities. Moreover, chelerythrine and 5-hydroxydecanoate, effective blockers of IPC and APC, annihilated IPC- and APC-induced enhanced postischemic responses of MAPKs. Finally, administration of PD98059 during ischemia-reperfusion diminished the protective effects of IPC and APC. Immunohistochemistry revealed increased ERK1/2 activity primarily in intercalated discs and nuclei and increased p38 MAPK activity in the sarcolemma and nuclei of IPC-treated hearts. Conclusions Although MAPKs may orchestrate cardioprotection as triggers and mediators in IPC, they are devoid of triggering, but they may have mediator effects in APC.

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