scholarly journals IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Guixi Mo ◽  
Xin Liu ◽  
Yiyue Zhong ◽  
Jian Mo ◽  
Zhiyi Li ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Caspase 1 ◽  
Intracellular Ca ◽  
Myocardial Ischemia Reperfusion

AbstractIntracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca2+ from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial enzymes, infarct area, Ca2+ level, NLRP3/Caspase-1, and pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block Ca2+ channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced Ca2+ overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca2+ overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca2+ level caused H/R-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits Ca2+ overload, thus alleviating pyroptosis and MI/R injury.

scholarly journals Sevoflurane Alleviates Myocardial Ischemia Reperfusion Injury by Inhibiting P2X7-NLRP3 Mediated Pyroptosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiaxuan Wu ◽  
Wenfeng Cai ◽  
Ruiming Du ◽  
Haiyang Li ◽  
Bin Wang ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Myocardial Ischemia ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Caspase 1 ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
In Cells

Myocardial ischemia is common in aging population. This study investigates the protective effect of Sevoflurane on myocardial ischemia reperfusion injury (MIRI) and its underlying mechanism. A total of 87 patients with a history of myocardial ischemia who underwent abdominal surgery with Sevoflurane general anesthesia were recruited in the study. The clinical data, blood pressure, heart rate, pressure-rate quotient (PRQ) and rate-pressure product (RPP) were recorded. Serum samples were collected and heart-type fatty acid binding protein (H-FABP), ischemia modified albumin (IMA), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were measured to observe whether Sevoflurane anesthesia had protective effect on myocardium. In addition, MIRI rats and hypoxia/reoxygenation (H/R) injury cell model was established using neonatal rat ventricular myocytes (NRVM). Rats or NRVM were pretreated with sevoflurane for 45min before hypoxia. The mRNA expression of purinergic receptor-7 (P2X7) and NLR family pyrin domain containing 3(NLRP3) were examined. The protein expression of P2X7, NLRP3, apoptosis-associated speck-like protein (ASC), cysteine aspartic acid specific protease-1(Caspase-1), Gasdermin-D (GSDMD), Bcl-2 Associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2) in myocardial tissue and cells were evaluated. The serum contents of IL-1β, IL-18, Malondialdehyde (MDA), Superoxide dismutase (SOD), Lactate dehydrogenase (LDH), Creatine kinase (CK), and Creatine kinase isoenzymes (CK-MB) were measured. The cellular localization and fluorescence intensity of NLRP3 and ASC in cells were detected. It was found that the secretion of IL-1β and IL-18 decreased in the patients. After I45 min/R3h in SD rats and H3h/R1h in NRVM, the protein expressions of P2X7, NLRP3, ASC, Caspase-1 and GSDMD were increased, the release of IL-1β, IL-18, CK, CK-MB, LDH and MDA were increased, and SOD activity was decreased. Sevoflurane treatment inhibited the high expression of P2X7, NLRP3, ASC, Caspase-1 and GSDMD, inhibited the release of LDH, CK,CK-MB and MDA in cells, and improved the activity of SOD, indicating that Sevoflurane alleviated the damage of MIRI of rats and H/R of NRVM, and had myocardial protective effect. Taken together, our study suggests that Sevoflurane inhibited the expression of IL-1β, IL-18 and GSDMD by inhibiting the P2X7-NLRP3 signaling pathway. It reduced the H/R injury of cardiomyocytes and protected the cardiac function by regulating inflammatory reaction and pyroptosis.

Resveratrol Nanoparticle Complex: Potential Therapeutic Applications in Myocardial Ischemia Reperfusion Injury

2020 ◽  
Vol 16 (3) ◽  
pp. 382-389
Author(s):  
Hong Zhou ◽  
Yungang Shan ◽  
Fei Tong ◽  
Yi Zhang ◽  
Jie Tang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Half Life ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Proton Nuclear Magnetic Resonance ◽  
Release Time ◽  
Rat Cardiomyocytes ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Resveratrol (RES) is a natural non-flavonoid polyphenol with cardioprotective activities, antioxidant, antiplatelet, and antiinflammatory. However, its low aqueous solubility, chemical stability, and oral bioavailability, as well as a short circulation half-life greatly limit its clinical applications. To overcome these limitations of RES, we synthesized a methoxy poly(ethylene glycol)-b-oligomerization(D, L-Leucine) (mPEG-b-O(D, L-Leu)) nanoparticle (NP) as the carrier of RES and evaluated the myocardial-protective effectiveness of this RES/NP complex in rat myocardial ischemia-reperfusion injury models. We gauged the characterization of the NP through proton nuclear magnetic resonance spectroscopy, gel permeation chromatography, transmission electron microscope, and Fourier transform infrared spectroscopy and then loaded RES on the nanocarrier by hydrophobic interactions under physiological pH to extend the release time of RES and prolong its circulation half-life. Subsequently, we used rat cardiomyocytes (H9C2 cells) and rat MI/RI model to investigate the relationship between drug composition and myocardial preservation properties. It was found that RES was encapsulated quickly and efficiently, and displayed an effectual loading-capacity and in vitro sustained-release. Anti-MI/RI effect of the RES/NP complex was found satisfactory in rat models in vivo using free RES as the control. This study suggested that NP may prove to be a potent nanocarrier to augment the pharmacotherapy of RES against MI/RI.

scholarly journals Simvastatin Improves Myocardial Ischemia Reperfusion Injury through KLF-Regulated Alleviation of Inflammation

2022 ◽  
Vol 2022 ◽  
pp. 1-6
Author(s):  
Tingju Wei ◽  
Jun Li ◽  
Guowei Fu ◽  
Hui Zhao ◽  
Chen Huang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Male Rats ◽  
Cell Counting ◽  
Inflammatory Factors ◽  
Simvastatin Treatment ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objective. To clarify the protective effect of simvastatin on myocardial ischemia reperfusion injury (MIRI) and the underlying mechanism. Materials and Methods. The MIRI model in rats was firstly constructed. Twenty-four male rats were randomly assigned into the sham group, ischemia-reperfusion (I/R) group, and simvastatin group, with 8 rats in each group. Contents of superoxide dismutase (SOD) and malondialdehyde (MDA), as well as serum levels of CK and inflammatory factors, in rats were determined by the enzyme-linked immunosorbent assay (ELISA). Lactate dehydrogenase (LDH) activity in the three groups was examined. Through flow cytometry and Cell Counting Kit-8 (CCK-8) assay, apoptosis and viability in each group were detected, respectively. Relative levels of HMGB1, Kruppel-like factor 2 (KLF2), eNOS, and thrombomodulin (TM) were finally determined. Results. Simvastatin treatment markedly enhanced SOD activity and reduced contents of MDA, LDH, and creatine kinase (CK) in MIRI rats. The increased apoptosis and decreased viability following MIRI were partially reversed by simvastatin treatment. Besides, MIRI resulted in the upregulation of inflammatory factors and chemokines. Their elevations were abolished by simvastatin. In MIRI rats, simvastatin upregulated KLF2 and p-eNOS. Conclusions. Simvastatin protects inflammatory response at post-MIRI through upregulating KLF2, thus improving cardiac function.

scholarly journals Nrf2 Promotes Inflammation in Early Myocardial Ischemia-Reperfusion via Recruitment and Activation of Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Haijian Zhang ◽  
Yifei Liu ◽  
Xiaoqing Cao ◽  
Wenmiao Wang ◽  
Xiaohong Cui ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Transcription Initiation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Interleukin 1 ◽  
Treatment Strategies ◽  
Underlying Mechanism ◽  
Inflammatory Factors ◽  
High Signature ◽  
Myocardial Ischemia Reperfusion

Cardiomyocyte apoptosis in response to inflammation is a primary cause of myocardial ischemia-reperfusion injury (IRI). Nuclear factor erythroid 2 like 2 (Nrf2) reportedly plays an important role in myocardial IRI, but the underlying mechanism remains obscure. Expression data from the normal heart tissues of mice or heart tissues treated with reperfusion for 6 h after ischemia (IR6h) were acquired from the GEO database; changes in biological function and infiltrating immune cells were analyzed. The binding between the molecules was verified by chromatin immunoprecipitation sequencing. Based on confirmation that early myocardial ischemia-reperfusion (myocardial ischemia/reperfusion for 6 hours, IR6h) promoted myocardial apoptosis and inflammatory response, we found that Nrf2, cooperating with Programmed Cell Death 4, promoted transcription initiation of C-C Motif Chemokine Ligand 3 (Ccl3) in myocardial tissues of mice treated with IR6h. Moreover, Ccl3 contributed to the high signature score of C-C motif chemokine receptor 1 (Ccr1)-positive macrophages. The high signature score of Ccr1-positive macrophages leads to the release of pro-inflammatory factors interleukin 1 beta and interleukin 6. This study is the first to elucidate the damaging effect of Nrf2 via remodeling of the immune microenvironment in early myocardial ischemia-reperfusion, which provides us with new perspectives and treatment strategies for myocardial ischemia-reperfusion.

scholarly journals Dunye Guanxinning Improves Acute Myocardial Ischemia-Reperfusion Injury by Inhibiting Neutrophil Infiltration and Caspase-1 Activity

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Q. G. Zhang ◽  
S. R. Wang ◽  
X. M. Chen ◽  
H. N. Guo ◽  
S. Ling ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Acute Myocardial Ischemia ◽  
Caspase 1 ◽  
Chinese Patent ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Acute myocardial infarction is the most serious manifestation of cardiovascular disease, and it is a life-threatening condition. Dunye Guanxinning (DG) is a protective traditional Chinese patent herbal medicine with high clinical efficacy and suitable for the treatment of myocardial infarction. However, the mechanism through which it is beneficial is unclear. In this study, we hypothesized that DG improves acute myocardial ischemia-reperfusion injury by inhibiting neutrophil infiltration and caspase-1 activity. We found that DG administration decreased infarct size and cardiomyocyte apoptosis and improved left ventricular ejection fraction, fractional shortening, end-systolic volume index, end-systolic diameter, and carotid arterial blood flow output in rats. DG administration also improved hemorheological parameters, myocardial damage biomarkers, and oxidative stress indexes. The findings showed that DG administration inhibited neutrophil infiltration and reduced the serum interleukin-1 beta (IL-1β) level and myocardial IL-1β maturation. Moreover, DG administration inhibited caspase-1 activity and activated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in rat hearts. These results suggested that DG administration inhibits inflammasome activity and IL-1β release through the AMPK pathway. Our findings support the clinical efficacy of DG and partially reveal its mechanism, which is beneficial for understanding the therapeutic effects of this protective traditional Chinese patent drug.

Abstract 14717: Endocrine Mechanisms against Ischemic Cardiomyocyte Calcification

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shu Liu ◽  
Brian Zhang ◽  
Yu H Wu
Keyword(s):  
Myocardial Ischemia ◽  
Actin Filaments ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Treatment Strategies ◽  
C Terminus ◽  
Intracellular Ca ◽  
Myocardial Ischemia Reperfusion ◽  
Underlying Mechanisms

Myocardial infarction causes cardiomyocyte calcification or deposition of hydroxyapatite crystals, structures disrupting cardiomyocytes and intensifying myocardial injury. While cardiomyocyte calcification is well recognized, the underlying mechanisms remain elusive and few treatment strategies have been established. Here, we test the hypotheses that annexins (ANXs), intracellular Ca++ carriers associated with the plasma membrane, contribute to ischemic cardiomyocyte calcification and the endocrine protein trefoil factor 3 (TFF3) is upregulated and released from the liver in ischemic myocardial injury, protecting ischemic cardiomyocytes from annexin-dependent calcification. Myocardial ischemia/reperfusion injury in 129s1/sv Imj mice caused translocation of ANXs A2, A3, A4, A5, and A7 from the cardiomyocyte membrane to α actin filaments in association with hydroxyapatite deposition to α actin filaments prior to cardiomyocyte death from 1 to 10 days. siRNA-mediated silencing of the ANX A2, A3, A4, A5, and A7 genes reduced the fraction of calcified cardiomyocytes at day 5 from 6.3+/-1.8% (control siRNA) to 2.1+/-0.6% in reference to the infarct area (p<0.01), suggesting a pro-calcification role for these ANXs. Myocardial injury caused upregulation and release of TFF3 from the liver. TFF3-/- mice exhibited intensified ischemic cardiomyocyte calcification (17.8+/-5.2%) compared to wildtype mice (5.6+/-2.3%, p<0.001), suggesting an anti-calcification role for TFF3. TFF3 was able to bind to ANXs A2, A3, A4, A5, and A7, demonstrated by TFF3 crosslinking assay and mass spectroscopy. ANX A2, A3, A4, A5, or A7 was able to co-immunoprecipitate with TFF3 in ischemic cardiomyocytes. Computational molecular interaction analyses by using the Autodocking software system showed TFF3 interaction with the ANX C-terminus, a structure binding to actin filaments. Myocardial administration of recombinant TFF3 reduced ANX-dependent cardiomyocyte calcification. These observations suggest that ANXs cause ischemic cardiomyocyte calcification by binding to α actin filaments and TFF3 is upregulated and released from the liver in myocardial ischemia, mitigating cardiomyocyte calcification by blocking ANX binding to actin filaments.

scholarly journals Inflammasome, pyroptosis, and cytokines in myocardial ischemia-reperfusion injury

2018 ◽  
Vol 315 (6) ◽  
pp. H1553-H1568 ◽  
Author(s):  
Stefano Toldo ◽  
Adolfo G. Mauro ◽  
Zachary Cutter ◽  
Antonio Abbate
Keyword(s):  
Myocardial Ischemia ◽  
Inflammatory Response ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Experimental Models ◽  
Receptor Protein ◽  
Caspase 1 ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Myocardial ischemia-reperfusion injury induces a sterile inflammatory response, leading to further injury that contributes to the final infarct size. Locally released danger-associated molecular patterns lead to priming and triggering of the NOD-like receptor protein 3 inflammasome and amplification of the inflammatory response and cell death by activation of caspase-1. We review strategies inhibiting priming, triggering, or caspase-1 activity or blockade of the inflammasome-related cytokines interleukin-1β and interleukin-18, focusing on the beneficial effects in experimental models of acute myocardial infarction in animals and the initial results of clinical translational research trials.

scholarly journals Genome-Wide Expression Profiling of Anoxia/Reoxygenation in Rat Cardiomyocytes Uncovers the Role of MitoKATPin Energy Homeostasis

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Song Cao ◽  
Yun Liu ◽  
Wenting Sun ◽  
Li Zhao ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Molecular Mechanism ◽  
Energy Homeostasis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Digital Gene Expression ◽  
Tca Cycle ◽  
Bioinformatic Analysis ◽  
Rat Cardiomyocytes ◽  
Myocardial Ischemia Reperfusion

Mitochondrial ATP-sensitive potassium channel (mitoKATP) is a common end effector of many protective stimuli in myocardial ischemia-reperfusion injury (MIRI). However, the specific molecular mechanism underlying its myocardial protective effect is not well elucidated. We characterized an anoxia/reoxygenation (A/R) model using freshly isolated adult rat cardiomyocytes. MitoKATPstatus was interfered with its specific opener diazoxide (DZ) or blocker 5-hydroxydecanote (5-HD). Digital gene expression (DGE) and bioinformatic analysis were deployed. Three energy metabolism related genes (MT-ND6, Idh2,andAcadl) were upregulated when mitoKATPopened. In addition, as many as 20 differentially expressed genes (DEGs) were significantly enriched in five energy homeostasis correlated pathways (PPAR, TCA cycle, fatty acid metabolism, and peroxisome). These findings indicated that mitoKATPopening in MIRI resulted in energy mobilization, which was confirmed by measuring ATP content in cardiomyocytes. These causal outcomes could be a molecular mechanism of myocardial protection of mitoKATPand suggested that the mitoKATPopening plays a physiologic role in triggering cardiomyocytes’ energy homeostasis during MIRI. Strategies of modulating energy expenditure during myocardial ischemia-reperfusion may be promising approaches to reduce MIRI.

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