scholarly journals Protective Effect of Ethyl Pyruvate against Myocardial Ischemia Reperfusion Injury through Regulations of ROS-Related NLRP3 Inflammasome Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Ji Hae Jun ◽  
Jae-Kwang Shim ◽  
Ju Eun Oh ◽  
Eun-Jung Shin ◽  
Eunah Shin ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ethyl Pyruvate ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Interleukin 1 ◽  
Neutrophil Infiltration ◽  
Inflammasome Activation ◽  
Myocardial Infarct Size ◽  
Nadph Oxidase 4

Emerging evidence indicates the pronounced role of inflammasome activation linked to reactive oxygen species (ROS) in the sterile inflammatory response triggered by ischemia/reperfusion (I/R) injury. Ethyl pyruvate (EP) is an antioxidant and conveys myocardial protection against I/R injury, while the exact mechanisms remain elusive. We aimed to investigate the effect of EP on myocardial I/R injury through mechanisms related to ROS and inflammasome regulation. The rats were randomly assigned to four groups: (1) sham, (2) I/R-control (IRC), (3) EP-pretreatment + I/R, and (4) I/R + EP-posttreatment. I/R was induced by a 30 min ligation of the left anterior descending artery followed by 4 h of reperfusion. EP (50 mg/kg) was administered intraperitoneally at 1 h before ischemia (pretreatment) or upon reperfusion (posttreatment). Both pre- and post-EP treatment resulted in significant reductions in myocardial infarct size (by 34% and 31%, respectively) and neutrophil infiltration. I/R-induced myocardial expressions of NADPH oxidase-4, carnitine palmitoyltransferase 1A, and thioredoxin-interacting protein (TXNIP) were mitigated by EP. EP treatment was associated with diminished inflammasome activation (NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like protein, and caspase-1) and interleukin-1β induced by I/R. I/R-induced phosphorylation of ERK and p38 were also mitigated with EP treatments. In H9c2 cells, hypoxia-induced TXNIP and NLRP3 expressions were inhibited by EP and to a lesser degree by U0126 (MEK inhibitor) and SB203580 (p38 inhibitor) as well. EP’s downstream protective mechanisms in myocardial I/R injury would include mitigation of ROS-mediated NLRP3 inflammasome upregulation and its associated pathways, partly via inhibition of hypoxia-induced phosphorylation of ERK and p38.

scholarly journals Daucosterol pretreatment ameliorates myocardial ischemia reperfusion injury via ROS-mediated NLRP3 inflammasome activation

2020 ◽  
Vol 19 (5) ◽  
pp. 1031-1036
Author(s):  
Guixiang Zhao ◽  
Xiaoyun Ma ◽  
Juledezi Hailati ◽  
Zhen Bao ◽  
Maerjiaen Bakeyi ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Myocardial Infarct Size ◽  
Nlrp3 Inflammasome Activation ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Purpose: To determine the involvement of NLRP3 signaling pathway in the preventive role of daucosterol in acute myocardial infarction (AMI).Methods: H9C2 cells were pretreated with daucosterol before hypoxia/reoxygenation (HR) injury. Myocardial ischemia reperfusion (IR) was established in male SD rats, followed by reperfusion. Myocardial infarct size was measured. The serum levels of creatine kinase (CK), lactate  dehydrogenase (LDH), total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were determined using commercial kits. NLRP3 inflammasome activation was assessed by western blotting.Results: Myocardial infarct size was smaller after IR injury in rats pretreated with daucosterol (10 and 50 mg/kg) than that pretreated with daucosterol (0 and 1 mg/kg). The increase in LDH, CK, and MDA levels after IR injury was reduced following daucosterol pretreatment. Reactive oxygen species (ROS) production increased, whereas T-SOD activity decreased after IR injury. These changes were prevented by pretreatment of daucosterol (10 and 50 mg/kg). Protein expression of NLRP3 inflammasome increased after IR injury in H9C2 cells while pretreatment with daucosterol inhibited the upregulation of NLRP3 inflammasome.Conclusion: The cardioprotective effect of daucosterol pretreatment appears to be mediated via the inactivation of ROS-related NLRP3 inflammasome, suggesting that daucosteol might be a potential therapeutic drug for AMI. Keywords: Daucosterol, Myocardial ischemia, Reperfusion injury, Reactive oxygen species, NLRP3 inflammasome

scholarly journals Nod-like Receptor Protein 3 (Nlrp3) Inflammasomes Inhibition by Metformin Limits Myocardial Ischemia/reperfusion Injury

2020 ◽  
Author(s):  
Jing Zhang ◽  
Liu Yang ◽  
Qin Zhang ◽  
Xing Shi ◽  
Fuzhou Hua ◽  
...  
Keyword(s):  
Infarct Size ◽  
Nlrp3 Inflammasome ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Myocardial Infarct Size ◽  
Ampk Phosphorylation ◽  
Nlrp3 Inflammasome Activation ◽  
Cardioprotective Effects

Abstract Background Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against myocardial I/R injury. In this study, we further examined the involvement of AMPK mediated activation of NLRP3 inflammasome in this cardioprotective effect of metformin. Methods Myocardial I/R injury was simulated in a rat heart Langendorff model and neonatal rat ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) to establish an in vitro model. Outcome measures included myocardial infarct size, hemodynamic monitoring, myocardial tissue injury, myocardial apoptotic index and the inflammatory response. myocardial infarct size and cardiac enzyme activities. Results First, we found that metformin postconditioning can not only significantly alleviated myocardial infarct size, attenuated cell apoptosis, and inhibited myocardial fibrosis. Furthermore, metformin activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and decreased NLRP3 inflammasome activation. In isolated NRVMs metformin increased cellular viability, decreased LDH activity and inhibited cellular apoptosis and inflammation. Importantly, inhibition of AMPK phosphorylation by Compound C (CC) resulted in decreased survival of cardiomyocytes mainly by inducing the release of inflammatory cytokines and increasing NLRP3 inflammasome activation. Finally, in vitro studies revealed that the NLRP3 activator nigericin abolished the anti-inflammatory effects of metformin in NRVMs, but it had little effect on AMPK phosphorylation. Conclusions Collectively, our study confirmed that metformin exerts cardioprotective effects by regulating myocardial I/R injury-induced inflammatory response, which was largely dependent on the enhancement of the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.

Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats

Pharmacology ◽  
2021 ◽  
Vol 106 (3-4) ◽  
pp. 189-201
Author(s):  
Shigang Qiao ◽  
Wen-jie Zhao ◽  
Huan-qiu Li ◽  
Gui-zhen Ao ◽  
Jian-zhong An ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Neonatal Rat ◽  
Ligand Docking ◽  
Autophagic Flux ◽  
Myocardial Infarct Size ◽  
Rat Cardiomyocytes

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

Abstract 300: Topical Application of IcyHot Reduces Myocardial Infarct Size in Rodents by a TRPA1-dependent Mechanism

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yun Wu ◽  
Yao Lu ◽  
Eric R Gross
Keyword(s):  
Infarct Size ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Calcium Influx ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Sprague Dawley ◽  
Area At Risk ◽  
Reactive Aldehydes

Toxic reactive aldehydes are formed during ischemia-reperfusion. The ion channel transient receptor potential ankryin 1 (TRPA1) is irreversibly modified by reactive aldehydes which can cause calcium influx and cell death. Here we tested whether topically applied creams containing a reversible TRPA1 agonist could reduce myocardial infarct size. Male Sprague-Dawley rats 8-10 weeks age were subjected to an in vivo myocardial ischemia-reperfusion model of 30 minutes of left anterior descending (LAD) coronary artery ischemia followed by 2 hours reperfusion. Prior to ischemia, rats were untreated or had 1g of cream applied to the abdomen. The creams tested were IcyHot, Bengay, Tiger Balm, or preparation H (Fig. 1A). Hearts were negatively stained for the area at risk and the infarct size was determined by using TTC staining (Fig. 1B). A subset of rodents prior to receiving IcyHot also received an intravenous bolus of the TRPA1 antagonist TCS-5861528 (1mg/kg) or AP-18 (1mg/kg). Interestingly, both IcyHot and Bengay reduced myocardial infarct size compared to untreated rodents (Fig. 1C and 1D IcyHot: 41±3%*, Bengay: 50±2%* versus control 62±1%, n=6/group, *P<0.001). Both preparation H and Tiger Balm failed to reduce myocardial infarct size (Tiger Balm: 63±2%, preparation H 59±2%). Giving a TRPA1 antagonist prior to IcyHot also blocked the reduction in infarct size. Our additional data also indicates the methyl salicylate (mint) in IcyHot and Bengay is the agent that limits myocardial infarct size. Since IcyHot and Bengay are safely used by humans, targeting TRPA1 by using products such as these could be quickly translatable and widely used to reduce ischemia-reperfusion injury.

scholarly journals The Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities of the Bauhinia Championii Flavone are Connected with Protection Against Myocardial Ischemia/Reperfusion Injury

2016 ◽  
Vol 38 (4) ◽  
pp. 1365-1375 ◽  
Author(s):  
Jie Jian ◽  
Feifei Xuan ◽  
Feizhang Qin ◽  
Renbin Huang
Keyword(s):  
Myocardial Ischemia ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tunel Staining ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

Background/Aims: Previous studies have demonstrated that Bauhinia championii flavone (BCF) exhibits anti-oxidative, anti-hypoxic and anti-stress properties. This study was designed to investigate whether BCF has a cardioprotective effect against myocardial ischemia/reperfusion (I/R) injuries in rats and to shed light on its possible mechanism. Methods: The model of I/R was established by ligating the left anterior descending coronary artery for 30 min, then reperfusing for 180 min. Hemodynamic changes were continuously monitored. The content of malondialdehyde (MDA) as well as the lactate dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were assessed. The release of interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA). Apoptosis of cardiomyocytes was determined by caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The expression of TLR4, NF-κBp65, Bcl-2 and Bax were detected by western blotting. Results: Pretreatment with BCF significantly reduced the serum levels of LDH, MDA and IL-6, but increased the activities of SOD and GSH-Px. It also attenuated myocardial infarct size, reduced the apoptosis rate and preserved cardiac function. Furthermore, BCF inhibited caspase-3 activity and the expression of TLR4, phosphorylated NF-κBp65 and Bax, but enhanced the expression of Bcl-2. Conclusion: These results provide substantial evidence that BCF exerts a protective effect on myocardial I/R injury, which may be attributed to attenuating lipid peroxidation, the inflammatory response and apoptosis.

Abstract 10246: Hydroxychloroquine Pretreatment Reduces Myocardial Ischemia-Reperfusion Injury: Role of Cardiac Extracellular-Signal-Regulated Kinase 5 and Autophagy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Feiyan Yang ◽  
Chang Yin ◽  
Lei Xi ◽  
Rakesh C Kukreja
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Beclin 1 ◽  
Myocardial Infarct Size ◽  
Western Blots ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Related Proteins

Background: Hydroxychloroquine (HCQ) is an antimalarial drug, which is also widely used to treat chronic rheumatologic diseases. Since HCQ was reported to inhibit cell autophagy and to activate extracellular-signal-regulated kinase 5 (ERK5) in vascular endothelial cells, we designed the current study to determine the effects of HCQ on cardiac ischemia-reperfusion (I-R) injury and post-I-R expression of ERK5 and autophagy marker proteins. Methods: Adult C57BL/6J mice of both genders were pretreated with HCQ (50 mg/kg, i.p.) 1 hour prior to isolation of the hearts, which were subjected to 30 min of no-flow global ischemia followed by 60 min of reperfusion in Langendorff mode. Ventricular function was continuously assessed and myocardial infarct size was determined at the end of I-R. Heart samples were collected following normoxic perfusion (no-ischemic controls), I-R, or I-R with HCQ for assessing ERK5 and autophagy-related proteins with Western blots. Results: HCQ pretreatment reduced infarct size significantly in the female hearts (P<0.05) as compared with the male hearts (Fig. A). Post-I-R cardiac function was better in HCQ-treated males (Fig. B). I-R resulted in a robust increase in total ERK5 (Fig. C) and phosphorylated ERK5 (Thr218/Tyr220) in both genders, which was abolished in HCQ-treated groups. Conversely, either I-R or HCQ did not affect the post-I-R cardiac expression of autophagy-related proteins (e.g., Atg5, Beclin-1, LC3II/LC3I ratio), except Beclin-1 phosphorylation was inhibited in HCQ-treated male hearts, but not females (Fig. D). Conclusions: Acute HCQ pretreatment affords cardioprotection against I-R injury in both genders. Interestingly, cardioprotective effects of HCQ are associated with a strong inhibitory effect on the induction of ERK5 following I-R in the heart, indicating a novel molecular mechanism underlying the HCQ-induced cardioprotection. However, the cardioprotective dose of HCQ has no major impact on cardiac autophagy.

Abstract 16381: Novel Thiol-activated H2S Donors Attenuate Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Chelsea Organ ◽  
Zhen Li ◽  
Yu Zhao ◽  
Chuntao Yang ◽  
Shashi Bhushan ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Sustained Release ◽  
Murine Model ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

Background: Hydrogen sulfide (H2S) protects against acute myocardial ischemia/reperfusion (MI/R) injury and heart failure by ameliorating oxidative stress, improving mitochondrial function, and attenuating apoptosis. One of the major limitations of currently available H2S donors is poor pharmacokinetics profiles that result in very rapid and uncontrolled H2S release. NSHD-1 and NSHD-2 are recently developed thiol-activated H2S donors designed for sustained release of H2S upon activation by molecules containing thiol groups such as cysteine and glutathione. We hypothesized that these novel H2S donors would generate H2S for extended periods and ameliorate myocardial cell death following MI/R in an in vivo murine model. Methods and Results: C57BL6/J male mice (10-12 weeks of age) were subjected to 45 minutes of MI followed by 24 hours of R. At the time of reperfusion, animals received Vehicle (0.5% THF), NSHD-1 (50 μg/kg and 100 μg/kg), or NSHD-2 (50 μg/kg) by direct intracardiac (i.c.) injection. In addition, at 4 hours of R, plasma was collected for troponin-I measurements. In preliminary studies we observed sustained release of H2S with both of these H2S donors. Myocardial infarct size was reduced by 35% (p < 0.01 vs. Vehicle) in mice treated with NSHD-1 (100 μg/kg), 43% (p < 0.05 vs. Vehicle) in mice treated with NSHD-2 (50 μg/kg), and 54% (p < 0.01 vs. Vehicle) in mice treated with NSHD-2 (100 μg/kg). Conclusions: NSHD-1 and NSHD-2 significantly attenuate MI/R injury in a murine model. Experiments are currently underway to further define the in vivo pharmacokinetics of H2S release from these agents, mechanisms of action, and safety profile.

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