Role of p38 inhibition in cardiac ischemia/reperfusion injury

Kumphune, Sarawut; Chattipakorn, Nipon

doi:10.1007/s00228-011-1193-2

Cited by 42 publications

(37 citation statements)

References 81 publications

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“…Recently, p38 has been represented as an emerging therapeutic target for the treatment of various conditions, including Alzheimer's disease, cardiac ischemia/reperfusion injury and chronic airways disease. 23,37,38 Thus, further efforts to discover new compounds that can specifically inhibit ASK1-p38 signaling for a prolonged period may lead to the development of novel strategies for the management of deteriorating diseases including retinal and optic nerve degeneration.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

et al. 2012

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Optic nerve injury (ONI) induces retinal ganglion cell (RGC) death and optic nerve atrophy that lead to visual loss. Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and has an important role in stress-induced RGC apoptosis. In this study, we found that ONI-induced p38 activation and RGC loss were suppressed in ASK1-deficient mice. Sequential in vivo retinal imaging revealed that post-ONI treatment with a p38 inhibitor into the eyeball was effective for RGC protection. ONI-induced monocyte chemotactic protein-1 production in RGCs and microglial accumulation around RGCs were suppressed in ASK1-deficient mice. In addition, the productions of tumor necrosis factor and inducible nitric oxide synthase in microglia were decreased when the ASK1-p38 pathway was blocked. These results suggest that ASK1 activation in both neural and glial cells is involved in neural cell death, and that pharmacological interruption of ASK1-p38 pathways could be beneficial in the treatment of ONI.

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Section: Discussionmentioning

confidence: 99%

Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

et al. 2012

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“…Previous studies demonstrated that the activation of the 38 kDa mitogen which activates protein kinase (p38 MAPK) during myocardial ischemia aggravates lethal cellular injury, particularly during I/R injury (Bogoyevitch et al, 1996;Clark et al, 2007;Kumphune et al, 2012). The pharmacological catalytic site inhibitor SB203580 has been shown to prevent p38 MAPK activation, and has beneficial effects on the heart, including reduced cardiomyocyte death and infarct size as well as attenuation of left ventricular function impairment in the myocardial I/R model (Barancik et al, 2000;Clark et al, 2007;Kumphune et al, 2010;Surinkaew et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of p38 MAPK activation protects cardiac mitochondria from ischemia/reperfusion injury

Kumphune

Surinkaew

Chattipakorn

et al. 2015

Pharmaceutical Biology

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Context: Cardiac cell death and fatal arrhythmias during myocardial ischemia/reperfusion (I/R) can be reduced by p38 MAPK inhibition. However, the effects of p38 MAPK inhibition on cardiac mitochondria have not been investigated. Objective: We tested the hypothesis that p38 MAPK inhibition at different times during I/R protects cardiac mitochondrial functions. Materials and methods: Adult Wistar rats were subjected to 30 min of left anterior descending coronary artery (LAD) occlusion, followed by 120 min of reperfusion. A 2 mg/kg bolus infusion of p38 MAPK inhibitor, SB203580, was given before or during ischemia, or at reperfusion. Mitochondrial function and ultrastructure were assessed and Western blots were performed. Results: Administration of SB203580 at any time point of I/R significantly attenuated the mitochondrial ultrastructure change, mitochondrial swelling, by increasing the absorbance at 540 nm (I/R control 0.42 ± 0.03; pretreatment 0.58 ± 0.04; during ischemia 0.49 ± 0.02; at reperfusion 0.51 ± 0.02, p50.05), similar to reactive oxygen species (ROS) generation (I/R control 1300 ± 48; pretreatment 1150 ± 30; during ischemia 1000 ± 50; at reperfusion 1050 ± 55, p50.05). Only SB203580 given before or during ischemia attenuated mitochondrial membrane depolarization (I/R control 0.78 ± 0.04; pretreatment 1.02 ± 0.03; during ischemia 1.05 ± 0.12, p50.05). In addition, pre-treatment of SB203580 significantly reduced the phosphorylation of p53, CREB, Bax, cytochrome c, and cleaved caspase 3. Discussion and conclusion: The results from this study showed for the first time that p38 MAPK inhibition protects mitochondria from I/R injury.

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“…The ERK1/2-PP1a pathway regulates the expression of phosphorylated PLB and SERCA2a [14]. The p38 MAPK pathway is another important pathway of the MAPK family, and p38 MAPK pathway inhibition could alleviate cardiomyocyte I/R injury and develop cardio-protective effects [15, 16]. In a recent randomized phase 2 trial in non-ST-segment elevation myocardial infarction, Newby et al observed that the use of a novel p38 mitogen-activated protein kinase inhibitor, losmapimod, was well tolerated in non-ST-segment elevation myocardial infarction patients and might improve outcomes after acute coronary syndromes [17].…”

Section: Introductionmentioning

confidence: 99%

Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion

Zhu

Luo

et al. 2017

Cell Physiol Biochem

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Background/Aims: A major challenge for current therapeutic strategies against ischemia/reperfusion (I/R) is the lack of effective drugs. Considering luteolin enhances the activity of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) to improve the systolic/diastolic function of rat hearts and cardiomyocytes during the I/R process, we studied the regulatory function of the p38 MAPK pathway in this protective mechanism. Methods: Isolated cardiomyocytes and perfused hearts were separately divided into five groups and used to investigate I/R. The phosphorylation of p38 and phospholamban (p-PLB), the levels and activity of SERCA2a and the levels of proteins related to apoptosis were measured. Apoptotic cells were assessed using the TUNEL assay. Single-cell shortening, Ca²⁺ transients, and the decay of the mitochondrial membrane potential (Δψm) were detected. Results: The p38 MAPK pathway was activated during the I/R process, and inhibiting it with SB203580 promoted p-PLB, which enhanced the activity of SERCA2a and relieved the calcium overload to promote the recovery of the Δψm and reduce cardiomyocyte apoptosis in I/R. Luteolin also suppressed the activation of the p38 MAPK pathway and showed cardioprotective effects during I/R injury. Conclusions: We conclude that luteolin enhances SERCA2a activity to improve systolic/diastolic function during I/R in rat hearts and cardiomyocytes by attenuating the inhibitive effects of the p38 pathway on p-PLB.

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Role of p38 inhibition in cardiac ischemia/reperfusion injury

Cited by 42 publications

References 81 publications

Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

Inhibition of p38 MAPK activation protects cardiac mitochondria from ischemia/reperfusion injury

Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion

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