Abstract 17056: Nanoparticles-mediated Targeting of Pioglitazone Reduces Myocardial Ischemia-reperfusion Injury and Cardiac Remodeling by Antagonizing Monocyte-mediated Inflammation in Preclinical Animal Models

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Masaki Tokutome ◽  
Tetsuya Matoba ◽  
Yasuhiro Nakano ◽  
Kaku Nakano ◽  
Kensuke Egashira
Keyword(s):  
Animal Models ◽  
Myocardial Ischemia ◽  
Cardiac Remodeling ◽  
Ischemia Reperfusion ◽  
Therapeutic Effects ◽  
Inflammatory Monocytes ◽  
Intravenous Treatment ◽  
Anti Inflammatory ◽  
Myocardial Ischemia Reperfusion ◽  
Preclinical Animal Models

Background: Monocyte-mediated inflammation is a major mechanism of myocardial ischemia-reperfusion (IR) injury and cardiac remodeling. However, no anti-inflammatory therapy has been developed for clinical myocardial IR injury. Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, has unique anti-inflammatory effects on monocyte/macrophage. Here we tested the hypothesis that nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and inflammatory monocytes ameliorates IR injury and cardiac remodeling in preclinical animal models. Methods and Results: We formulated poly (lactic acid/glycolic acid) nanoparticle containing pioglitazone (Pio-NPs). In mouse IR model, nanoparticles were delivered predominantly to circulating monocytes and to cardiomyocytes and macrophages in the IR heart. Intravenous treatment with Pio-NPs containing ≥0.1 mg/kg of pioglitazone at the time of reperfusion reduced IR injury, which was canceled by the pretreatment with PPARγ antagonist GW9662 (Fig. A). In contrast, pioglitazone solution at doses up to 3.0 mg/kg showed no therapeutic effects (Fig. A). Pio-NPs reduced inflammatory gene expression and inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart (Fig. B). Pio-NPs showed no therapeutic effects in mice lacking CCR2. In a mouse model of myocardial infarction, intravenous treatment with Pio-NPs for 3 days after LAD ligation attenuated cardiac remodeling, improved cardiac function, and reduced recruitment of macrophage and polarization of macrophages toward M2 phenotype (Fig. C, D). Finally, in a mini-pig model of myocardial IR injury, Pio-NPs induced cardioprotection from IR injury, indicating the pre-clinical proof of concept. Conclusion: Nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and monocytes can be developed as a novel modality that offers organ protection by antagonizing monocyte-mediated inflammation in acute MI.

Abstract 260: Nanoparticle-mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-reperfusion Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Gentaro Ikeda ◽  
Tetsuya Matoba ◽  
Ayako Ishikita ◽  
Kensuke Egashira
Keyword(s):  
Myocardial Ischemia ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Flow Cytometric Analysis ◽  
Poly Lactic Acid ◽  
Therapeutic Effects ◽  
Cyclophilin D ◽  
Inflammatory Monocytes ◽  
Myocardial Ischemia Reperfusion

Background: Targeting one mediator of myocardial ischemia-reperfusion (IR) injury failed to reduce infarct size in clinical trials, suggesting the necessity of the innovative strategy to target more than 2 mediators simultaneously. 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 mPTP and monocytes confers additive cardioprotection against IR injury. Methods and Results: We produced mice deficient with both cyclophilin D (CypD, a key molecule for mPTP opening) and CCR2 (a receptor for monocyte chemoattractant protein-1), and found that the double-KO mice displayed dramatic reduction in myocardial IR injury model (Fig. A). Flow cytometric analysis and 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. In CypD mice, Pitava-NP reduced recruitment of Ly6Chigh inflammatory monocytes and showed therapeutic effects (Fig. B). In contrast, CsA-NP reduced IR injury in CCR2-KO mice. Simultaneous treatment with CsA-NP and Pitava-NP at the time of reperfusion showed additive reduction in IR injury in wild-type mice (Fig. C). Conclusions: Nanoparticle-mediated simultaneous targeting to mitochondria and inflammatory monocytes can be developed as a novel therapeutic strategy in IR injury.

Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia–reperfusion in vivo

2012 ◽  
Vol 107 (4) ◽  
Author(s):  
Martinus I. F. J. Oerlemans ◽  
Jia Liu ◽  
Fatih Arslan ◽  
Krista Ouden ◽  
Ben J. Middelaar ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Cardiac Remodeling ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion

scholarly journals S100A8/A9 Enhances Immunomodulatory and Tissue-Repairing Properties of Human Amniotic Mesenchymal Stem Cells in Myocardial Ischemia-Reperfusion Injury

2021 ◽  
Vol 22 (20) ◽  
pp. 11175
Author(s):  
Tzu-Jou Chen ◽  
Yen-Ting Yeh ◽  
Fu-Shiang Peng ◽  
Ai-Hsien Li ◽  
Shinn-Chih Wu
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myocardial Ischemia ◽  
Conditioned Medium ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Therapeutic Effects ◽  
Paracrine Factors ◽  
Amniotic Mesenchymal Stem Cells ◽  
Myocardial Ischemia Reperfusion

Paracrine factors of human mesenchymal stem cells (hMSCs) have the potential of preventing adverse cardiac remodeling after myocardial infarction (MI). S100A8 and S100A9 are calcium-binding proteins playing essential roles in the regulation of inflammation and fibrous tissue formation, and they might modulate the paracrine effect of hMSCs. We isolated human amniotic mesenchymal stem cells (hAMSCs) and examined the changes in the expression level of regulatory genes of inflammation and fibrosis after hAMSCs were treated with S100A8/A9. The anti-inflammatory and anti-fibrotic effects of hAMSCs pretreated with S100A8/A9 were shown to be superior to those of hAMSCs without S100A8/A9 pretreatment in the cardiomyocyte hypoxia/reoxygenation experiment. We established a murine myocardial ischemia/reperfusion model to compare the therapeutic effects of the conditioned medium of hAMSCs with or without S100A8/A9 pretreatment. We found the hearts administered with a conditioned medium of hAMSCs with S100A8/A9 pretreatment had better left ventricular systolic function on day 7, 14, and 28 after MI. These results suggest S100A8/A9 enhances the paracrine therapeutic effects of hAMSCs in aspects of anti-inflammation, anti-fibrosis, and cardiac function preservation after MI.

scholarly journals Light Emitting Diode Therapy Protects against Myocardial Ischemia/Reperfusion Injury through Mitigating Neuroinflammation

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Songyun Wang ◽  
Qinyu Luo ◽  
Hui Chen ◽  
Jingyu Huang ◽  
Xuemeng Li ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Light Emitting Diode ◽  
Ischemia Reperfusion ◽  
Microglia Activation ◽  
Light Emitting ◽  
M2 Microglia ◽  
Led Therapy ◽  
Anti Inflammatory ◽  
Myocardial Ischemia Reperfusion

Background. Neuroinflammation plays a key role in myocardial ischemia-reperfusion (I/R) injury. Previous studies showed that light-emitting diode (LED) therapy might improve M2 microglia activation and brain-derived neurotrophic factor (BDNF) expression, thereby exerting anti-inflammatory effects. Therefore, we hypothesized that LED therapy might reduce myocardial I/R injury by neuroinflammation modulation. Objective. To explore the effect of LED therapy on myocardial I/R-induced injury and seek the underlying mechanism. Methods. Thirty rats were randomly divided into three groups: Control group (without LED treatment or myocardial I/R, n=6), I/R group (with myocardial I/R only, n=12), and LED+I/R group (with myocardial I/R and LED therapy, n=12). Electrocardiogram was recorded continuously during the procedure. In addition, brain tissue was extracted for BDNF, Iba1, and CD206 analyses, and heart tissue for myocardial injury (ischemic size and infarct size), IL-4 and IL-10 mRNA analysis. Results. In comparison with the I/R group, the ischemia size and the infarct size were significantly attenuated by LED therapy in the LED+I/R group. Meanwhile, the microglia activation induced by I/R injury was prominently attenuated by LED treatment either. And it is apparent that there was also an increase in the beneficial neuroinflammation markers (BDNF and CD206) in the paraventricular nucleus (PVN) in the LED+I/R group. Furthermore, the anti-inflammatory cytokines, IL-4 and IL-10, were greatly decreased by I/R while improved by LED treatment in myocardium. Conclusion. LED therapy might reduce neuroinflammation in PVN and decrease myocardium injury by elevating BDNF and M2 microglia.

Abstract 99: Conditional Depletion of CD11c + Cells Attenuates Myocardial Ischemia-Reperfusion Injury in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jun Li ◽  
Mozow Y Zuidema ◽  
Cuihua Zhang ◽  
Michael A. Hill ◽  
Feng Gao
Keyword(s):  
Dendritic Cells ◽  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
Diphtheria Toxin ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inflammatory Monocytes ◽  
Myocardial Ischemia Reperfusion ◽  
Inflammatory Macrophages

Excessive infiltration of pro-inflammatory monocytes /macrophages early after myocardial ischemia/reperfusion (MI/R) contributes to myocardial injury and cardiac dysfunction. We tested the hypothesis that conditional depletion of pro-inflammatory macrophages and dendritic cells may dampen excessive inflammatory response in the infarct myocardium, and thus attenuate MI/R injury. To achieve this, we took advantage of CD11c-diphtheria toxin receptor (DTR) transgenic mice, which allow for selective and conditional ablation of CD11c + cells for 2-3 days after diphtheria toxin administration. CD11c-DTR mice with conditional deficiency of CD11c + cells and wild type (WT) mice were subjected to MI/R (30 min /48 h). CD11c-DTR mice showed decreased infiltration of CD11c + dendritic cells and CD11c + F4/80 + macrophages in the I/R heart, reduced infarct size, attenuated myocardium apoptosis and improved cardiac function compared with those in WT mice. Moreover, inflammatory cytokines, such as TNF-α, MCP-1 and IFN-γ in the infracted myocardium as well as myocardial nitrotyrosine level, an index of oxidative and nitrative stresses, were dramatically decreased in CD11c-DTR mice than those in WT mice. These data indicate that the decreased infiltration of pro-inflammatory macrophages /dendritic cells and subsequent ameliorated inflammation may contribute to attenuated reperfusion injury and better reserved cardiac function in CD11c-DTR mice. This may provide potential novel strategies to target pro-inflammatory cells to reduce detrimental effects while sparing the beneficial wound healing roles of the recruited macrophages.

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.

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