Inhibition of p38 Mitogen-Activated Protein Kinase Decreases Cardiomyocyte Apoptosis and Improves Cardiac Function After Myocardial Ischemia and Reperfusion

L., Xin; Kumar, Sanjay; Gao, Feng; Louden, Calvert; Lopez, Bernard L.; Christopher, Theodore A.; Wang, Chuanlin; Lee, John C.; Feuerstein, Giora; Yue, Tian‐Li

doi:10.1161/01.cir.99.13.1685

Cited by 463 publications

(353 citation statements)

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“…Thus, the effects of MK2 deficiency may be underestimated due to the confounding effects on p38 MAPK content. Since ischemic activation of p38 MAPK is thought to contribute to myocardial injury (Saurin et al 2000;Mackay and Mochly-Rosen 1999;Ma et al 1999), the reduced p38 MAPK expression would be expected to attenuate ischemic damage. Although total p38 MAPK was reduced, activation was readily detectable, and the relative amount of p38 MAPK phosphorylation in response to ischemia (as percent of baseline) was similar in MK2 −/− and MK2 +/+ hearts.…”

Section: Effect Of Mapkapk-2 Deficiency and Sb203580 On Downstream Simentioning

confidence: 99%

“…However, it is generally agreed that the intraischemic activation of p38(α)MAPK contributes to myocardial injury, since infarct size following ischemia/reperfusion can be reduced by the pyridinyl imidazole compound SB203580 which is a potent and selective inhibitor of p38 MAPK. However, the underlying intracellular mechanism (s) leading to p38 MAPK activation during ischemia and its role in injury remain to be well clarified (Bassi et al 2008;Clark et al 2007;Saurin et al 2000;Mackay and MochlyRosen 1999;Ma et al 1999).…”

Section: Introductionmentioning

confidence: 99%

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MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

Gorog¹,

Jabr²,

Tanno³

et al. 2009

Cell Stress and Chaperones

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MAPKAPK-2 (MK2) is a protein kinase activated downstream of p38-MAPK which phosphorylates the small heat shock proteins HSP27 and αB crystallin and modulates p38-MAPK cellular distribution. p38-MAPK activation is thought to contribute to myocardial ischemic injury; therefore, we investigated MK2 effects on ischemic injury and p38 cellular localization using MK2-deficient mice (KO). Immunoblotting of extracts from Langendorffperfused hearts subjected to aerobic perfusion or global ischemia or reperfusion showed that the total and phosphorylated p38 levels were significantly lower in MK2 −/− compared to MK2 +/+ hearts at baseline, but the ratio of phosphorylated/total p38 was similar. These results were confirmed by cellular fractionation and immunoblotting for both cytosolic and nuclear compartments. Furthermore, HSP27 and αB crsytallin phosphorylation were reduced to baseline in MK2 −/− hearts. On semiquantitative immunofluorescence laser confocal microscopy of hearts during aerobic perfusion, the mean total p38 fluorescence was significantly higher in the nuclear compared to extranuclear (cytoplasmic, sarcomeric, and sarcolemmal compartments) in MK2 +/+ hearts. However, although the increase in phosphorylated p38 fluorescence intensity in all compartments following ischemia in MK2 +/+ hearts was lost in MK2 −/− hearts, it was basally elevated in nuclei of MK2 −/− hearts and was similar to that seen during ischemia in MK2 +/+ hearts. Despite these differences, similar infarct volumes were recorded in wild-type MK2 +/+ and MK2 −/− hearts, which were decreased by the p38 inhibitor SB203580 (1 μM) in both genotypes. In conclusion, p38 MAPKinduced myocardial ischemic injury is not modulated by MK2. However, the absence of MK2 perturbs the cellular distribution of p38. The preserved nuclear distribution of active p38 MAPK in MK2 −/− hearts and the conserved

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Section: Effect Of Mapkapk-2 Deficiency and Sb203580 On Downstream Simentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

Gorog¹,

Jabr²,

Tanno³

et al. 2009

Cell Stress and Chaperones

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“…Via its signalling cascade, the p38 MAPK modulates genes that regulate myocyte apoptosis, cellular hypertrophy, cardiac fibrosis, and cardiac cytokine-mediated inflammation [11][12][13]. Because the p38 MAPK is not only upregulated and phosphorylated by ischaemia [14], but also, for example, by angiotensin II [15], oxidative stress [16], and high glucose levels [10], inhibition of p38 MAPK could be a potent new therapeutic option for treatment of diabetic cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus

et al. 2006

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Aims/hypothesis We investigated the effect of SB 203580, a pharmacological inhibitor of p38 mitogen-activated protein kinase (MAPK), on cardiac inflammation, cardiac fibrosis, and left ventricular function using an animal model of diabetic cardiomyopathy. Materials and methods Diabetes mellitus was induced by streptozotocin (50 mg/kg i.p. for 5 days) in 20 C57/BL6J mice. Diabetic mice were treated daily with the p38 MAPK inhibitor SB 203580 (1 mg/kg daily, n=10) or with placebo (n=10) and were compared to non-diabetic controls. Left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. The parameters for systolic function were the end systolic pressure-volume relationship (ESPVR) and the left ventricular end systolic pressure. The parameters for diastolic function were the left ventricular end diastolic pressure and the end diastolic pressure-volume relationship (EDPVR). Cardiac tissue was analysed by ELISA for the protein content of the cytokines TNF-α, IL6, IL1-β, and TGF-β1. Phosphorylation of MAPK p38 was analysed by western blot, and the total cardiac collagen content was analysed by Sirius red staining.

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“…The mechanisms underlying this phenomenon remain unclear. During the ischemia-reperfusion process, many kinases within the ischemic area are activated, including extracellular signal-regulated kinase (ERK)1/2, c-Jun NH 2 -terminal kinase (JNK)1/2, and p38 mitogen-activated protein kinase (p38 MAPK) (2,22,25). p38 MAPK, a stress-activated serine/threonine protein kinase belonging to the MAPK superfamily, plays a major role in regulating apoptosis, cytokine production, transcriptional regulation, and cytoskeletal reorganization (36).…”

mentioning

confidence: 99%

“…Many stimuli, including ultraviolet light, irradiation, heat shock, ischemia, hypoxia, osmotic stress, proinflammatory cytokines, and certain mitogens can activate this kinase. Recent evidence suggests that p38 MAPK plays a major role in the myocardial ischemia-reperfusion injury as that its targeted inhibition reduces the cardiac injury and cell death following ischemia-reperfusion in vivo (14,18,22). On the other hand, prior activation of this kinase, similar to recurrent, short-duration ischemia, preconditions the myocardium against subsequent ischemia-reperfusion injury (20,27,37).…”

mentioning

confidence: 99%

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

Chai¹,

Wu²,

Li³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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. Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 294: E183-E189, 2008. First published November 14, 2007 doi:10.1152/ajpendo.00571.2007.-Myocardial ischemiareperfusion injury contributes significantly to morbidity and mortality in patients with diabetes. Insulin decreases myocardial infarct size in animals and the rate of apoptosis in cultured cells. Ischemia-reperfusion activates p38 mitogen-activated protein kinase (MAPK), which regulates cellular apoptosis. To examine whether p38 MAPK affects insulin's cardioprotection against ischemia-reperfusion injury, we studied overnight-fasted adult male rats by use of an in vivo rat model of myocardial ischemia-reperfusion. A euglycemic clamp (3 mU ⅐ min Ϫ1 ⅐ kg Ϫ1 ) was begun either 10 min before ischemia (Insulin BI), 5 min before reperfusion (InsulinBR), or 30 min after the onset of reperfusion (Insulin AR ), and continued until the end of the study. Compared with saline control, insulin decreased the infarct size in both Insulin BI (P Ͻ 0.001) and InsulinBR (P Ͻ 0.02) rats but not in Insulin AR rats. The ischemic area showed markedly increased phosphorylation of p38 MAPK compared with the nonischemic area in saline animals. Acute activation of p38 MAPK with anisomycin (2 mg/kg iv 10 min before ischemia) had no effect on infarct size in saline rats. However, it completely abolished insulin's protective effect in Insulin BI and InsulinBR rats. Activation of p38 MAPK by anisomycin was associated with marked and persistent elevation in IRS-1 serine phosphorylation. Treatment of animals with SB-239063, a potent and specific inhibitor of p38 MAPK, 10 min before reperfusion enabled insulin-mediated myocardial protection in Insulin AR rats. We conclude that insulin protects myocardium against ischemiareperfusion injury when given prior to ischemia or reperfusion, and activation of p38 MAPK abolishes insulin's cardioprotective effect.

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Inhibition of p38 Mitogen-Activated Protein Kinase Decreases Cardiomyocyte Apoptosis and Improves Cardiac Function After Myocardial Ischemia and Reperfusion

Abstract: Background-Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in apoptotic cell death.The role of p38 MAPK in myocardial injury caused by ischemia/reperfusion, an extreme stress to the heart, is unknown.

Cited by 463 publications

References 24 publications

MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

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