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.

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 Luteolin Exerts Cardioprotective Effects through Improving Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats during Ischemia/Reperfusion In Vivo

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Changsheng Nai ◽  
Haochen Xuan ◽  
Yingying Zhang ◽  
Mengxiao Shen ◽  
Tongda Xu ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Signaling Pathway ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Myocardial Infarct Size ◽  
Akt Signaling Pathway ◽  
Cardioprotective Effects

The flavonoid luteolin exists in many types of fruits, vegetables, and medicinal herbs. Our previous studies have demonstrated that luteolin reduced ischemia/reperfusion (I/R) injury in vitro, which was related with sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. However, the effects of luteolin on SERCA2a activity during I/R in vivo remain unclear. To investigate whether luteolin exerts cardioprotective effects and to monitor changes in SERCA2a expression and activity levels in vivo during I/R, we created a myocardial I/R rat model by ligating the coronary artery. We demonstrated that luteolin could reduce the myocardial infarct size, lactate dehydrogenase release, and apoptosis during I/R injury in vivo. Furthermore, we found that luteolin inhibited the I/R-induced decrease in SERCA2a activity in vivo. However, neither I/R nor luteolin altered SERCA2a expression levels in myocardiocytes. Moreover, the PI3K/Akt signaling pathway played a vital role in this mechanism. In conclusion, the present study has confirmed for the first time that luteolin yields cardioprotective effects against I/R injury by inhibiting the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo, independent of SERCA2a protein level regulation. SERCA2a activity presents a novel biomarker to assess the progress of I/R injury in experimental research and clinical applications.

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.

Abstract 127: Txnip-Mediated NLRP3 Inflammasome Activation as a Novel Mechanism of Myocardial Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yi Liu ◽  
Lijian Zhang ◽  
Yan Qu ◽  
Chao Gao ◽  
Jingyi Liu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Myocardial Ischemia Reperfusion

As an inhibitor of the antioxidant thioredoxin, thioredoxin-interacting protein (Txnip) is linked to insulin resistance. NLRP3 inflammasome, a major regulator of innate immunity, has been reported to be activated by Txnip, thus contributing to the pathogenesis of type 2 diabetes mellitus. However, the role of Txnip and its NLRP3 inflammasome activation in the myocardial ischemia/reperfusion (MI/R) injury has not been previously investigated. C57BL/6J mice were subjected to 30 min of ischemia and 3 or 24 hrs of reperfusion. The ischemic heart exhibited increased Txnip and NLRP3 expressions, increased interaction between Txnip and NLRP3 (by immunoprecipitation, 1.8-fold increase over sham), and increased IL-1β, IL-18 and caspase-1 expressions (%increase: 80%, 77% and 110%, respectively) (n=8, all P <0.05). Compared with vehicle group, those mice either receiving intramyocardial small-interfering RNA (siRNA) injection to specifically knockdown the myocardial NLRP3 or intraperitoneal injection of the inflammasome inhibitor (BAY 11-7082) exhibited significantly improved cardiac function (by 28% and 25%), decreased the infarct size (by 40% and 38%), and decreased the cardiomyocytes apoptosis (all P <0.05). NLRP3 knockdown or inflammasome inhibitor also decreased the inflammatory cells infiltration (macrophages and neutrophils) and cytokines (TNF-α, INF-γ and IL-6) production (all P <0.05). To elucidate the role of Txnip in the NLRP3 activation in MI/R, intramyocardial injection of Txnip siRNA was performed to specifically knockdown the myocardial Txnip expression. Compared with vehicle, the Txnip knockdown significantly decreased Txnip/NLRP3 interaction and NLRP3activation as evidenced by lower expressions of IL-1β and caspase-1, decreased inflammatory cells infiltration and cytokines expressions, and consequently decreased the myocardial infarct size and increased the heart function (all P <0.05). Collectively, we demonstrated for the first time that Txnip mediatedNLRP3 inflammasome activation is a novel mechanism of MI/R injury. Interventions targeted to blocking the activation of NLRP3 by inhibiting Txnip may have therapeutic potential for preventing MI/R injury.

scholarly journals Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Scott M. Filippone ◽  
Arun Samidurai ◽  
Sean K. Roh ◽  
Chad K. Cain ◽  
Jun He ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Reperfusion Therapy ◽  
Myocardial Infarct Size ◽  
Ribosomal Protein S6 ◽  
Cardioprotective Effects ◽  
Fractional Shortening

Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg) or DMSO (7.5%) was injected intracardially at the onset of reperfusion. Post-I/R survival (87%) and cardiac function (fractional shortening, FS:28.63±3.01%) were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS:17.4±2.6%). Rapamycin caused significant reduction in myocardial infarct size (IS:26.2±2.2%) and apoptosis (2.87±0.64%) as compared to DMSO-treated mice (IS:47.0±2.3%; apoptosis:7.39±0.81%). Rapamycin induced phosphorylation of AKT S473 (target of mTORC2) but abolished ribosomal protein S6 phosphorylation (target of mTORC1) after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38.

scholarly journals NLRP3 Inflammasome Activation-Mediated Pyroptosis Aggravates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Zhen Qiu ◽  
Shaoqing Lei ◽  
Bo Zhao ◽  
Yang Wu ◽  
Wating Su ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Ischemia ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Myocardial Infarct Size ◽  
Nlrp3 Inflammasome Activation ◽  
Myocardial Ischemia Reperfusion

The reactive oxygen species- (ROS-) induced nod-like receptor protein-3 (NLRP3) inflammasome triggers sterile inflammatory responses and pyroptosis, which is a proinflammatory form of programmed cell death initiated by the activation of inflammatory caspases. NLRP3 inflammasome activation plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Our present study investigated whether diabetes aggravated MI/R injury through NLRP3 inflammasome-mediated pyroptosis. Type 1 diabetic rat model was established by intraperitoneal injection of streptozotocin (60 mg/kg). MI/R was induced by ligating the left anterior descending artery (LAD) for 30 minutes followed by 2 h reperfusion. H9C2 cardiomyocytes were exposed to high glucose (HG, 30 mM) conditions and hypoxia/reoxygenation (H/R) stimulation. The myocardial infarct size, CK-MB, and LDH release in the diabetic rats subjected to MI/R were significantly higher than those in the nondiabetic rats, accompanied with increased NLRP3 inflammasome activation and increased pyroptosis. Inhibition of inflammasome activation with BAY11-7082 significantly decreased the MI/R injury.In vitrostudies showed similar effects, as BAY11-7082 or the ROS scavenger N-acetylcysteine, attenuated HG and H/R-induced H9C2 cell injury. In conclusion, hyperglycaemia-induced NLRP3 inflammasome activation may be a ROS-dependent process in pyroptotic cell death, and NLRP3 inflammasome-induced pyroptosis aggravates MI/R injury in diabetic rats.

Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat

2006 ◽  
Vol 290 (6) ◽  
pp. H2644-H2647 ◽  
Author(s):  
Micah S. Johnson ◽  
Russell L. Moore ◽  
David A. Brown
Keyword(s):  
At Risk ◽  
Sex Differences ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Female Rats ◽  
Male Rats ◽  
Myocardial Infarct Size ◽  
Sprague Dawley

This study was conducted to examine the relationship between myocardial ATP-sensitive potassium (KATP) channels and sex differences in myocardial infarct size after in vitro ischemia-reperfusion (I/R). Hearts from adult male and female Sprague-Dawley rats were excised and exposed to an I/R protocol (1 h of ischemia, followed by 2 h of reperfusion) on a modified Langendorff apparatus. Hearts from female rats showed significantly smaller infarct sizes than hearts from males (23 ± 4 vs. 40 ± 5% of the zone at risk, respectively; P < 0.05). Administration of HMR-1098, a sarcolemmal KATP channel blocker, abolished the sex difference in infarct size (42 ± 4 vs. 45 ± 5% of the zone at risk in hearts from female and male rats, respectively; P = not significant). Further experiments showed that blocking the KATP channels in ischemia, and not reperfusion, was sufficient to increase infarct size in female rats. These data demonstrate that sarcolemmal KATP channels are centrally involved in mechanisms that underlie sex differences in the susceptibility of the intact heart to I/R injury.

scholarly journals Ophiopogonin D Reduces Myocardial Ischemia-Reperfusion Injury via Upregulating CYP2J3/EETs in Rats

2018 ◽  
Vol 49 (4) ◽  
pp. 1646-1658 ◽  
Author(s):  
Xiaoyan Huang ◽  
Yuguang Wang ◽  
Yi Wang ◽  
Liang Yang ◽  
Jia Wang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Cardioprotective Effects ◽  
Myocardial Ischemia Reperfusion ◽  
Apoptotic Effects

Background/Aims: Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase (CYP) metabolites of arachidonic acid and have multiple cardiovascular effects. Ophiopogonin D (OP-D) is an important effective monomeric component in Shenmai injection (SM-I). Both have been reported to have a variety of biological functions, including anti-inflammatory, anti-oxidant, and anti-apoptotic effects. We previously demonstrated that OP-D–mediated cardioprotection involves activation of CYP2J2/3 and enhancement of circulating EETs levels in vitro and can be developed as a novel drug for the therapy of myocardial ischemia-reperfusion (MI/R) injury. We therefore hypothesized that the protective effects of OP-D and SM-I against MI/R injury are associated with increased expression of CYP2J3 and enhanced circulating 11,12-EET levels in vivo. Methods: A rat model of MI/R injury was generated by ligation of the left anterior descending coronary artery for 40 min, followed by reperfusion for 2 h to determine the protective effects and potential mechanisms of OP-D and SM-I. Electrocardiogram and ultrasonic cardiogram were used to evaluate cardiac function; 2,3,5-triphenyltetrazolium chloride was used to measure myocardial infarct size; hematoxylin and eosin staining and transmission electron microscopy were used to observe the morphology of myocardial tissue; and the expression of related proteins in the mechanistic study was observed by western blot analysis. Results: We found that OP-D and SM-I exert protective effects on MI/R injury, including regulation of cardiac function, reduction of lactate dehydrogenase and creatine kinase production, attenuation of myocardial infarct size, and improvement of the recovery of damaged myocardial structures. We found that OP-D and SM-I activate CYP2J3 expression and increase levels of circulating 11,12-EET in MI/R-injured rats. Conclusion: We tested the hypothesis that the cardioprotective effects of OP-D and SM-I on MI/R injury are associated with increased expression of CYP2J3 and enhanced circulating 11,12-EET levels in rats. Taken together, our results show that the effects of OP-D and SM-I were also mediated by the activation of the PI3K/Akt/eNOS signaling pathway, while inhibition of the NF-κB signaling pathway and antioxidant and anti-apoptotic effects were involved in the cardioprotective effects of OP-D and SM-I.

scholarly journals Dexmedetomidine attenuates myocardial ischemia-reperfusion injury in vitro by inhibiting NLRP3 Inflammasome activation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yaru Huang ◽  
Xiaotong Sun ◽  
Zhaodong Juan ◽  
Rui Zhang ◽  
Ruoguo Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Cardiac Fibroblasts ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Related Proteins

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro. Methods We established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined. Results Dexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1β, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1β and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. Conclusion Dexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.

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