Inhibition of p38 MAPK During Ischemia, But Not Reperfusion, Effectively Attenuates Fatal Arrhythmia in Ischemia/Reperfusion Heart

Surinkaew, Sirirat; Kumphune, Sarawut; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

doi:10.1097/fjc.0b013e318279b7b1

Cited by 57 publications

(71 citation statements)

References 46 publications

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“…These findings suggest that p53 and CREB are downstream molecules of p38 MAPK that were not activated via HSP27, or could possibly be regulated by other unidentified signaling pathways that could be affected by SB203580. Furthermore, SB203580 given at reperfusion could only reduce cleaved caspase 3 levels without any change in the Bax, Bcl2, and cytochrome c. The reduction of cleaved caspase 3 level could sufficiently attenuate the apoptotic pathway, which is consistent with the results from our previous report that SB203580 given at the onset of reperfusion also reduced the infarct size (Surinkaew et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

“…However, giving SB203580 at the onset of reperfusion failed to prevent the loss of mitochondrial membrane potential, in which cardiac mitochondrial depolarization plays an important role in arrhythmogenesis (O'Rouke, 2000). These findings could provide the mechanistic explanation of our previous report, which demonstrated from our previous study that the infarct size reduction was found at all-time points of SB203580 treatment, but treatment of SB203580 before or during ischemia, but not at reperfusion, decreased the incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) incidence (Surinkaew et al, 2013). Although SB203580 showed a protective effect on cardiac mitochondrial swelling, ROS production, and mitochondrial membrane potential depolarization, the mitochondrial respiration was not performed and was considered a limitation of this study.…”

Section: Discussionsupporting

confidence: 52%

“…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). Recently, we reported the cardioprotective effects of SB203580 administered at different time courses of I/R injury models, and demonstrated that SB203580 given at each time course could reduce the infarct size even when given at the reperfusion onset (Surinkaew et al, 2013). Interestingly, SB203580 not only reduced the infarct size but also decreased I/R-induced arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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

Kumphune

Surinkaew

Chattipakorn

et al. 2015

Pharmaceutical Biology

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“…Left ventricular tissues were lysed with extraction buffer (20 mmol l −1 Tris-HCl, 1 mmol l −1 Na 3 VO 4 and 5 mmol l −1 NaF), separated by electrophoresis on 10% sodium dodecyl sulfatepolyacrylamide gel and transferred onto nitrocellulose membranes (Surinkaew et al 2013). Immunoblots were blocked for 1 h with 5% non-fat dry milk in Tris-buffered saline (pH 7.4) containing 0.1% Tween 20.…”

Section: Western Blot Analysismentioning

confidence: 99%

Dual T‐type and L‐type calcium channel blocker exerts beneficial effects in attenuating cardiovascular dysfunction in iron‐overloaded thalassaemic mice

Kumfu

Chattipakorn

Fucharoen

et al. 2016

Experimental Physiology

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New Findings r What is the central question of this study? Head-to-head comparison of the therapeutic efficacy among commercial iron chelators and a dual T-(TTCC) and L-type calcium channel (LTCC) blocker on cardiac function, mitochondrial function and the protein expression of cardiac iron transporters in thalassaemic mice in iron-overloaded conditions has not been assessed. r What is the main finding and its importance?The dual TTCC and LTCC blocker efonidipine could provide broad beneficial effects in the heart, liver, plasma and mitochondria in both wild-type and thalassaemic mice in iron-overloaded conditions. Its beneficial effects are of the same degree as the three commercial iron chelators currently used clinically. It is possible that efonidipine could be an alternative choice in patients unable to take iron chelators for the treatment of iron-overload conditions. Iron chelation therapy is a standard treatment in thalassaemia patients; however, its poor cardioprotective efficacy and serious side-effects are a cause for concern. Previous studies have shown that treatment with L-type calcium channel (LTCC) blockers or dual T-type calcium channel (TTCC) and LTCC blockers decreases cardiac iron and improves cardiac dysfunction in an iron-overloaded rodent model. Currently, the head-to-head comparison of therapeutic efficacy among commercial iron chelators, a dual TTCC and LTCC blocker and an LTCC blocker on cardiac function, mitochondrial function and the protein expression of cardiac iron transporters in thalassaemic mice in an iron-overloaded state has never been investigated. An iron-overloaded state was induced in β-thalassaemic and wild-type mice. Cardiac iron overload was induced to a greater extent than in a previous study by feeding the mice with an iron-enriched diet for 4 months. Then, an LTCC blocker (amlodipine) or a dual TTCC and LTCC blocker (efonidipine) or one of the commercial iron chelators (deferoxamine, deferasirox or deferiprone) was administered for 1 month with continuous iron feeding. All treatments reduced cardiac iron deposition and improved mitochondrial and cardiac dysfunction in both types of mice. Only efonidipine and the iron chelators reduced liver iron accumulation, liver malondialdehyde and plasma malondialdehyde in these mice. Although all pharmacological interventions reduced cardiac iron deposition, they did not alter the protein expression levels of

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“…This adverse effect has been shown to be even more severe in obese insulin resistance, resulting in increased infarct size and increased myocardial susceptibility to ischemia-reperfusion (I/R) injury [3], [4]. I/R injury has been shown to associate with fatal cardiac arrhythmias [5]. Cardiac mitochondrial damage has been implicated as one of the major factors responsible for myocardial cell death from I/R injury [6].…”

Section: Introductionmentioning

confidence: 99%

Combined Vildagliptin and Metformin Exert Better Cardioprotection than Monotherapy against Ischemia-Reperfusion Injury in Obese-Insulin Resistant Rats

et al. 2014

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BackgroundObese-insulin resistance caused by long-term high-fat diet (HFD) consumption is associated with left ventricular (LV) dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R) injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats.MethodologyMale Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV), LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43) were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats.ConclusionAlthough both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate.

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Inhibition of p38 MAPK During Ischemia, But Not Reperfusion, Effectively Attenuates Fatal Arrhythmia in Ischemia/Reperfusion Heart

Cited by 57 publications

References 46 publications

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

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

Dual T‐type and L‐type calcium channel blocker exerts beneficial effects in attenuating cardiovascular dysfunction in iron‐overloaded thalassaemic mice

Combined Vildagliptin and Metformin Exert Better Cardioprotection than Monotherapy against Ischemia-Reperfusion Injury in Obese-Insulin Resistant Rats

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