scholarly journals Effect of Ligustrazine on Myocardial Ischemia/reperfusion Injury Through Upregulating UCP3

2020 ◽  
Author(s):  
Ke-fu Zhu ◽  
Wu Shao-ze ◽  
Hong-feng Jin ◽  
Jiang-jie Lou ◽  
Ying-zheng Wen ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Troponin I ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Uncoupling Protein ◽  
Ischemia Reperfusion ◽  
Blue Staining ◽  
Sham Operation ◽  
Myocardial Ischemia Reperfusion ◽  
Ucp3 Expression

Abstract Background: The study aimed to investigate whether ligustrazine, a traditional Chinese medicine, could attenuate myocardial ischemia/reperfusion (I/R) injury and explore the potential mechanism.Methods: 32 Sprague-Dawley rats were divided equally into four groups: sham operation (S); (I/R); I/R + ligustrazine preconditioning (Lig); I/R + ligustrazine preconditioning + mitochondrial permeability transition pore (mPTP) opener lonidamine (LND) (Lig + LND). Myocardial I/R model was established and ligustrazine was administered intraperitoneally 5 min prior to ischemia, LND was administered intraperitoneally 10 min prior to reperfusion. The infarct area (IA) was measured by Evans blue staining, where levels of Myocardial injury markers, malondialdehyde (MDA), superoxide dismutase (SOD), adenosine triphosphate (ATP) were detected. RT-PCR and Western Blot were adopted to measure the uncoupling protein 3 (UCP3) expression.Results: Compared to I/R group, the IA/area at risk (AAR) in Lig, and Lig + LND groups were significantly decreased, UCP3 levels of mRNA and protein were increased (P < 0.05). Compared to Lig group, the IA/AAR in Lig + LND group was significantly increased (P < 0.05). Ligustrazine pretreatment increased SOD, ATP activity, and decreased cardiac troponin I (cTnI), creatine kinase-muscle/brain (CK-MB), lactate dehydrogenase (LDH) and MDA activities. The effect of ligustrazine was reversed by LND.Conclusion: The present results indicated that ischemic preconditioning of ligustrazine might protect myocardium against I/R injury through upregulating UCP3 expression.

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.

scholarly journals Dexmedetomidine Attenuates Myocardial Ischemia-Reperfusion Injury in Diabetes Mellitus by Inhibiting Endoplasmic Reticulum Stress

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jinjie Li ◽  
Ying Zhao ◽  
Nan Zhou ◽  
Longyun Li ◽  
Kai Li
Keyword(s):  
Endoplasmic Reticulum ◽  
Myocardial Ischemia ◽  
Endoplasmic Reticulum Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sham Operation ◽  
Sham Operation Group ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objective. With the increasing incidence of diabetes mellitus (DM) combined with myocardial ischemia, how to reduce myocardial ischemia-reperfusion injury in DM patients has become a major problem faced by clinicians. We investigated the therapeutic effects of dexmedetomidine (DEX) on myocardial ischemia-reperfusion injury in DM rats and its effect on endoplasmic reticulum stress. Methods. SD rats with SPF grade were randomly divided into 6 groups: non-DM rats were divided into the sham operation group (NDM-S group), ischemia-reperfusion group (NDM-IR group), and dexmedetomidine group (NDM-DEX group); DM rats were divided into the diabetic sham operation group (DM-S group), diabetes-reperfusion group (DM-IR group), and diabetes-dexmedetomidine (DM-DEX) group, with 10 rats in each group. Then the effects of DEX on the changes of CK-MB and cTnT levels were examined. The effects of myocardial pathological damage and myocardial infarct size were detected. The apoptosis of cardiomyocytes was detected. The apoptosis of heart tissue cells was also tested through the expressions of cleaved caspase-3, Bcl-2, and Bax proteins. The expression of endoplasmic reticulum stress-related proteins GRP78, CHOP, ERO1α, ERO1β, and PDI was examined. The hypoxia/reoxygenation (H/R) injury cell model was established, the effects of DEX, DEX+ ERS agonist on cell apoptosis was also detected. Results. The myocardial damage of DM-IR was more severe than that of NDM-IR rats. DEX could reduce the expression of CK-MB and cTnT, reduce pathological damage, and reduce scar formation and improve fibrosis. DEX can reduce the expression of GRP78, CHOP, ERO1α, ERO1β, and PDI proteins in vivo and in vitro. And the effect of DEX on cell apoptosis could be blocked by ERS agonist. Conclusion. DEX attenuates myocardial ischemia-reperfusion injury in DM rats and H/R injury cell, which is associated with the reduction of ERS-induced cardiomyocyte apoptosis.

scholarly journals Captopril Pretreatment Produces an Additive Cardioprotection to Isoflurane Preconditioning in Attenuating Myocardial Ischemia Reperfusion Injury in Rabbits and in Humans

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Yi Tian ◽  
Haobo Li ◽  
Peiyu Liu ◽  
Jun-mei Xu ◽  
Michael G. Irwin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Volatile Anesthetic ◽  
Myocardial Inflammation ◽  
Sham Operation ◽  
Replacement Surgery ◽  
Myocardial Apoptosis ◽  
Myocardial Ischemia Reperfusion

Background.Pretreatment with the angiotensin-converting inhibitor captopril or volatile anesthetic isoflurane has, respectively, been shown to attenuate myocardial ischemia reperfusion (MI/R) injury in rodents and in patients. It is unknown whether or not captopril pretreatment and isoflurane preconditioning (Iso) may additively or synergistically attenuate MI/R injury.Methods and Results.Patients selected for heart valve replacement surgery were randomly assigned to five groups: untreated control (Control), captopril pretreatment for 3 days (Cap3d), or single dose captopril (Cap1hr, 1 hour) before surgery with or without Iso (Cap3d+Iso and Cap1hr+Iso). Rabbit MI/R model was induced by occluding coronary artery for 30 min followed by 2-hour reperfusion. Rabbits were randomized to receive sham operation (Sham), MI/R (I/R), captopril (Cap, 24 hours before MI/R), Iso, or the combination of captopril and Iso (Iso+Cap). In patients, Cap3d+Iso but not Cap1hr+Iso additively reduced postischemic myocardial injury and attenuated postischemic myocardial inflammation. In rabbits, Cap or Iso significantly reduced postischemic myocardial infarction. Iso+Cap additively reduced cellular injury that was associated with improved postischemic myocardial functional recovery and reduced myocardial apoptosis and attenuated oxidative stress.Conclusion.A joint use of 3-day captopril treatment and isoflurane preconditioning additively attenuated MI/R by reducing oxidative stress and inflammation.

scholarly journals 5′-N-Ethylcarboxamido Adenosine Attenuates Myocardial Ischemia/Reperfusion Injury In Type 2 Diabetic Rats Through A2AR/PKCα/miR-15a Signaling

2021 ◽  
Author(s):  
Chao Chen ◽  
Jianjuan Ke ◽  
Huang Ding ◽  
Chengjun Hu ◽  
Zhenggang Wang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Caspase 3 ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Diabetic Rat ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Type 2 Diabetic

Abstract Background/aims: Type 2 diabetes mellitus aggravates myocardial ischemia/reperfusion injury (MI/RI). Activation of adenosine receptors (ARs) confer to attenuated MI/RI in nondiabetic animals and human. However, this effects and mechanism of ARs in the type 2 diabetic state are still unknown. In present study, we established a type 2 diabetic rat in vivo myocardial ischemia/reperfusion (MI/R) model to evaluate the effect of ARs on MI/RI with a focus on the A2A adenosine receptor (A2 AR) -mediated cardioprotective effects. Methods: Type 2 diabetic rat were subjected to myocardial infarction by LAD ligation in situ and randomly received ARs agonist and/or antagonists or vehicle treatment. After 2h marker of the extent of myocardial damage(ejection fraction of the LV, Infarct size, plasma cardiac troponin I) were measured and pro- and anti-apoptotic signals (protein kinase Cα，Bcl-2, Bax, miR-15), and marker of apoptosis execution (cleaved caspase-3, TUNEL) were quantified in the infarcted myocardium.Results: non-selective adenosine receptor agonist 5′-(N-ethylcarboxamido) adenosine treatment attenuates MI/RI, improve post-MI/R left ventricular function, limit infarct size, reduce cardiac troponin I release, reduce myocardial apoptosis, up-regulates bcl2 and down-regulates miR-15a, bax and cleaved caspase-3 expression; This protective effects were attenuated by pretreatment with selective A2AR antagonist ZM241385 or PKCα-selective inhibitor Go6976; and duplicated by treatment with A2AR-selective agonist CGS21680 or PKCα-potent activator PMA.Conclusions: NECA reduces MI/RI in T2DM rats via the A2AR/PKCα/miR-15a signaling pathway; NECA is a useful target candidate for the treatment of MI/RI in patient with type 2diabetes.

Abstract 15162: Nanoparticle-Mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-Reperfusion Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Gentaro Ikeda ◽  
Tetsuya Matoba ◽  
Kaku Nakano ◽  
Kenji Sunagawa ◽  
Kensuke Egashira
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Flow Cytometric Analysis ◽  
Poly Lactic Acid ◽  
Cyclophilin D ◽  
Inflammatory Monocytes ◽  
Myocardial Ischemia Reperfusion

Backcround: Targeting one mediator of myocardial ischemia-reperfusion (IR) injury failed to successfully reducing infarct size in clinical trials; therefore, an innovative approach may be to target more than 2 mediators at a time. Previously, we have engineered poly(lactic acid/glycolic acid) nanoparticle containing cyclosporine A (CsA-NP) and pitavastatin (Pitava-NP), and reported that the former inhibits the opening of mitochondrial permeability transition pore (mPTP) and the latter reduces monocyte-mediated inflammation in IR hearts. Here we tested the hypothesis that nanoparticle-mediated simultaneous targeting to mitochondria and monocytes confers additive and ultimate cardioprotection against IR injury. Methods and Result: In a murine model of myocardial IR injury, simultaneous treatment with CsA-NP and Pitava-NP at the time of reperfusion showed additive reduction in IR injury (infarct size) in wild-type mice (Fig. A). In cyclophilin D (CypD, a key regulatory molecule for mPTP opening)-KO mice, Pitava-NP reduced IR injury and recruitment of Ly6Chigh inflammatory monocytes whereas CsA-NP had no therapeutic effcts (Fig. B). In contrast, CsA-NP reduced IR injury in CCR2 (a receptor for monocyte chemoattractant protein-1)-KO mice. Flow cytometric analysis revealed that Pitava-NP, but not CsA-NP, inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart. We then produced CypD/CCR2 -knockout mice and found that the double-KO mice displayed dramatic reduction in IR injury (Fig. C). Fluorescence molecular tomography showed that inflammation was markedly inhibited in CCR2-KO and CypD/CCR2-KO mice while residual inflammation was noted in CypD-KO mice (Fig. D). Conclusions: Nanoparticle-mediated simultaneous targeting to mitochondria and inflammatory monocytes can be developed as a novel therapeutic strategy that offers ultimately adequate cardioprotection in acute myocardial infarction and other clinical settings.

Abstract 263: Therapeutic Potential of a Novel Necrosis Inhibitor in Myocardial Ischemia-reperfusion Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hyun-Jai Cho ◽  
In-Chang Hwang ◽  
Ju-Young Kim ◽  
Hak Seung Lee ◽  
Jaewon Lee ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Protective Effect ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Ros Scavenging ◽  
In Vivo Models ◽  
Myocardial Ischemia Reperfusion

Background: Reperfusion, although essential for salvage of ischemic myocardium, paradoxically causes a wide variety of injuries. Opening of mitochondrial permeability transition pore (mPTP) and Ca 2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. We aimed to investigate the protective role of a novel necrosis inhibitor (NecroX-7; NecX) against myocardial I/R injury, using in vitro and in vivo models. Methods and Results: In H9C2 rat cardiomyoblasts exposed to hypoxia-reoxygenation stress, the main mechanism of cell death was not apoptosis but necrosis, which was prevented mainly by NecX, the necrosis inhibitor, but not by Z-VAD-fmk, the apoptosis inhibitor. The protective effect of NecX was based on its potent ROS scavenging activity, especially on mitochondrial ROS which is one of the major inducers of mPTP opening. NecX preserved mitochondrial membrane potential, mitochondrial structure, through prevention of Ca 2+ influx and inhibition of the opening of mPTP. Inhibition of necrosis by NecX was accompanied by reduction of phospho-p38 MAPK and phospho-JNK, and decrease of HMGB1. Using Sprague-Dawley rats exposed to myocardial ischemia for 45 minutes followed by reperfusion, we compared therapeutic efficacies of NecX and Ciclosporin A (CsA) with 5% dextrose (control), each administrated 5 minutes before reperfusion. NecX markedly inhibited myocardial necrosis, reduced fibrotic area and attenuated the release of cardiac enzymes, compared to dextrose and CsA. Additionally, NecX preserved systolic function and prevented pathologic dilatory remodeling of left ventricle. Conclusion: The novel necrosis inhibitor has a significant protective effect against myocardial I/R injury, indicating that it is a promising candidate for cardioprotective adjunctive measure on top of reperfusion therapy. Clinical implication: We are trying to translate this experimental data into patients. A phase I clinical trial confirmed the safety profiles of NecX [NCT01737424] and a phase II trial for STEMI patients (NEXsteMI trial) is ongoing [NCT02070471].

MicroRNA-141 regulates the expression level of ICAM-1 on endothelium to decrease myocardial ischemia-reperfusion injury

2015 ◽  
Vol 309 (8) ◽  
pp. H1303-H1313 ◽  
Author(s):  
Rong Rong Liu ◽  
Jun Li ◽  
Jiu Yu Gong ◽  
Fang Kuang ◽  
Jia Yun Liu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Expression Level ◽  
Novel Target ◽  
Myocardial Ischemia Reperfusion

A growing number of studies have suggested microRNAs (miRNAs) are involved in the modulation of myocardial ischemia-reperfusion (MI/R) injury; however, the role of endogenous miRNAs targeting endothelial cells (ECs) and its interaction with ICAM-1 in the setting of MI/R remain poorly understood. Our microarray results showed that miR-146a, miR-146b-5p, miR-155*, miR-155, miR-497, and miR-451 were significantly upregulated, whereas, miR-141 and miR-564 were significantly downregulated in the ECs challenged with TNF-α for 6 h. Real-time PCR analyses additionally validated that the expression levels of miR-146a, miR-155*, and miR-141 were consistent with the microarray results. Then, ICAM-1 was identified as a novel target of miR-141 by Target Scan software and the reporter gene system. Further functional experiments showed that elevated levels of miR-141 inhibited ICAM-1 expression and diminished leukocytes adhesion to ECs in vitro. In an in vivo murine model of MI/R injury, pretreatment with miR-141 mimics through the tail vein downregulated the expression level of ICAM-1 in heart and attenuated MI/R injury as evidenced by decreased infarct size and decline of serum cardial troponin I (cTnI) and lactate dehydrogenase (LDH) concentration. The cardioprotective effects of miR-141 mimics may be attributed to the decreased infiltration of CD11b+ cells and F4/80+ macrophages into ischemic myocardium tissue. In conclusion, our results demonstrate that miR-141, as a novel repressor of ICAM-1, is involved in the attenuation of MI/R injury via antithetical regulation of ICAM-1 and inflammatory cells infiltration. Thus miR-141 may constitute a new therapeutic target in the setting of ischemic heart disease.

scholarly journals Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: implications for pharmacological cardioprotection

2018 ◽  
Vol 315 (5) ◽  
pp. H1341-H1352 ◽  
Author(s):  
Giuseppe Paradies ◽  
Valeria Paradies ◽  
Francesca Maria Ruggiero ◽  
Giuseppe Petrosillo
Keyword(s):  
Myocardial Ischemia ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Morphology ◽  
Myocardial Ischemia Reperfusion

Mitochondrial dysfunction plays a central role in myocardial ischemia-reperfusion (I/R) injury. Increased reactive oxygen species production, impaired electron transport chain activity, aberrant mitochondrial dynamics, Ca2+ overload, and opening of the mitochondrial permeability transition pore have been proposed as major contributory factors to mitochondrial dysfunction during myocardial I/R injury. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a pivotal role in multiple mitochondrial bioenergetic processes, including respiration and energy conversion, in mitochondrial morphology and dynamics as well as in several steps of the apoptotic process. Changes in CL levels, species composition, and degree of oxidation may have deleterious consequences for mitochondrial function with important implications in a variety of pathophysiological conditions, including myocardial I/R injury. In this review, we focus on the role played by CL alterations in mitochondrial dysfunction in myocardial I/R injury. Pharmacological strategies to prevent myocardial injury during I/R targeting mitochondrial CL are also examined.

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