scholarly journals Nanotoxicology of Dendrimers in the Mammalian Heart: ex vivo and in vivo Administration of G6 PAMAM Nanoparticles Impairs Recovery of Cardiac Function Following Ischemia-Reperfusion Injury

2020 ◽  
Vol Volume 15 ◽  
pp. 4393-4405
Author(s):  
Fawzi Babiker ◽  
Ibrahim F Benter ◽  
Saghir Akhtar
Keyword(s):  
Cardiac Function ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Mammalian Heart ◽  
In Vivo Administration

scholarly journals mTOR‐mediated calcium transients affect cardiac function in ex vivo ischemia–reperfusion injury

2021 ◽  
Vol 9 (6) ◽  
Author(s):  
Briana K. Shimada ◽  
Naaiko Yorichika ◽  
Jason K. Higa ◽  
Yuichi Baba ◽  
Motoi Kobayashi ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Calcium Transients

scholarly journals Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury

Circulation ◽  
2021 ◽  
Author(s):  
Meredith A. Redd ◽  
Sarah E. Scheuer ◽  
Natalie J. Saez ◽  
Yusuke Yoshikawa ◽  
Han Sheng Chiu ◽  
...  
Keyword(s):  
Ion Channel ◽  
Reperfusion Injury ◽  
Electromechanical Coupling ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Genetic Ablation ◽  
Organ Level

Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0-6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. Methods: We used genetic and pharmacological methods to investigate the role of acid sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole organ level. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and post-conditioning therapeutic agents. Results: Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using hiPSC-CMs in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction (MI) and two models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as pre- or post-conditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Conclusions: Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

scholarly journals Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury

2013 ◽  
Vol 304 (7) ◽  
pp. H966-H982 ◽  
Author(s):  
Akihiro Masuzawa ◽  
Kendra M. Black ◽  
Christina A. Pacak ◽  
Maria Ericsson ◽  
Reanne J. Barnett ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Reperfusion Injury ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Creatine Kinase Mb ◽  
Myocardial Energetics

Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 106/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased ( P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2–8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.

The role of microRNA in modulating myocardial ischemia-reperfusion injury

2011 ◽  
Vol 43 (10) ◽  
pp. 534-542 ◽  
Author(s):  
Yumei Ye ◽  
Jose R. Perez-Polo ◽  
Jinqiao Qian ◽  
Yochai Birnbaum
Keyword(s):  
Heart Disease ◽  
Reperfusion Injury ◽  
Fas Ligand ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Therapeutic Targets ◽  
In Vitro Models

MicroRNAs (miRNAs) are small (∼22 nt) noncoding single-stranded RNA molecules that downregulate gene expression. Studies have shown that miRNAs control diverse aspects of heart disease, including hypertrophy, remodeling, heart failure, and arrhythmia. Recently, several studies have suggested that miRNAs contribute to ischemia-reperfusion injury by altering key signaling elements, thus making them potential therapeutic targets. By altering the expression of various key elements in cell survival and apoptosis [such as phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Bcl-2, Mcl-1, heat shock protein (HSP)60, HSP70, HSP20, programmed cell death 4 (Pdcd4), LRRFIP1, Fas ligand (FasL), Sirt-1, etc.], miRNAs alter the response to ischemia-reperfusion injury. Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction. Thus miRNAs could be potential therapeutic targets for the treatment of heart disease. Inhibiting miRNAs by antisense strategies or pharmacological approaches is likely to emerge as an alternative and safe method for conferring short- and intermediate-term protection against ischemia-reperfusion injury.

scholarly journals Antioxidant network expression abrogates oxidative posttranslational modifications in mice

2011 ◽  
Vol 300 (5) ◽  
pp. H1960-H1970 ◽  
Author(s):  
R. Mital ◽  
W. Zhang ◽  
M. Cai ◽  
Z. M. Huttinger ◽  
L. A. Goodman ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Fatty Acid Binding ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Antioxidant enzymatic pathways form a critical network that detoxifies ROS in response to myocardial stress or injury. Genetic alteration of the expression levels of individual enzymes has yielded mixed results with regard to attenuating in vivo myocardial ischemia-reperfusion injury, an extreme oxidative stress. We hypothesized that overexpression of an antioxidant network (AON) composed of SOD1, SOD3, and glutathione peroxidase (GSHPx)-1 would reduce myocardial ischemia-reperfusion injury by limiting ROS-mediated lipid peroxidation and oxidative posttranslational modification (OPTM) of proteins. Both ex vivo and in vivo myocardial ischemia models were used to evaluate the effect of AON expression. After ischemia-reperfusion injury, infarct size was significantly reduced both ex vivo and in vivo, ROS formation, measured by dihydroethidium staining, was markedly decreased, ROS-mediated lipid peroxidation, measured by malondialdehyde production, was significantly limited, and OPTM of total myocardial proteins, including fatty acid-binding protein and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a, was markedly reduced in AON mice, which overexpress SOD1, SOD3, and GSHPx-1, compared with wild-type mice. These data demonstrate that concomitant SOD1, SOD3, and GSHPX-1 expression confers marked protection against myocardial ischemia-reperfusion injury, reducing ROS, ROS-mediated lipid peroxidation, and OPTM of critical cardiac proteins, including cardiac fatty acid-binding protein and SERCA2a.

scholarly journals Sulforaphane Elicits Protective Effects in Intestinal Ischemia Reperfusion Injury

2020 ◽  
Vol 21 (15) ◽  
pp. 5189
Author(s):  
Zhiquan Chen ◽  
Annika Mohr ◽  
Barbara Heitplatz ◽  
Uwe Hansen ◽  
Andreas Pascher ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Cellular Interactions ◽  
Morphological Alterations ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia reperfusion injury (IRI) is an inherent, unavoidable event of intestinal transplantation, contributing to allograft failure and rejection. The inflammatory state elicited by intestinal IRI is characterized by heightened leukocyte recruitment to the gut, which is amplified by a cross-talk with platelets at the endothelial border. Sulforaphane (SFN), a naturally occurring isothiocyanate, exhibits anti-inflammatory characteristics and has been shown to reduce platelet activation and block leukocyte adhesion. Thus, the aim of this study was to investigate protective effects and mechanism of action of SFN in a murine model of intestinal IRI. Intestinal IRI was induced by superior mesenteric artery occlusion for 30 min, followed by reperfusion for 2 h, 8 h or 24 h. To investigate cellular interactions, leukocytes were in vivo stained with rhodamine and platelets were harvested from donor animals and ex vivo stained. Mice (C57BL/6J) were divided into three groups: (1) control, (2) SFN treatment 24 h prior to reperfusion and (3) SFN treatment 24 h prior to platelet donation. Leukocyte and platelet recruitment was analyzed via intravital microscopy. Tissue was analyzed for morphological alterations in intestinal mucosa, barrier permeability, and leukocyte infiltration. Leukocyte rolling and adhesion was significantly reduced 2 h and 8 h after reperfusion. Mice receiving SFN treated platelets exhibited significantly decreased leukocyte and platelet recruitment. SFN showed protection for intestinal tissue with less damage observed in histopathological and ultrastructural evaluation. In summary, the data presented provide evidence for SFN as a potential therapeutic strategy against intestinal IRI.

scholarly journals The Role of Tetrahydrobiopterin and Dihydrobiopterin in Ischemia/Reperfusion Injury When Given at Reperfusion

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Qian Chen ◽  
Elizabeth Eun Jung Kim ◽  
Katrina Elio ◽  
Christopher Zambrano ◽  
Samuel Krass ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Saline Control ◽  
Early Reperfusion ◽  
Product Profile ◽  
Major Factors

Reduced nitric oxide (NO) bioavailability and increased oxidative stress are major factors mediating ischemia/reperfusion (I/R) injury. Tetrahydrobiopterin (BH4) is an essential cofactor of endothelial NO synthase (eNOS) to produce NO, whereas dihydrobiopterin (BH2) can shift the eNOS product profile from NO to superoxide, which is further converted to hydrogen peroxide (H2O2) and cause I/R injury. The effects ofBH4andBH2on oxidative stress and postreperfused cardiac functions were examined in ex vivo myocardial and in vivo femoral I (20 min)/R (45 min) models. In femoral I/R,BH4increased NO and decreasedH2O2releases relative to saline control, and these effects correlated with improved postreperfused cardiac function. By contrast,BH2decreased NO release relative to the saline control, but increasedH2O2release similar to the saline control, and these effects correlated with compromised postreperfused cardiac function. In conclusion, these results suggest that promoting eNOS coupling to produce NO and decreaseH2O2may be a key mechanism to restore postreperfused organ function during early reperfusion.

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