scholarly journals Preventive Effect of Canstatin against Ventricular Arrhythmia Induced by Ischemia/Reperfusion Injury: A Pilot Study

2021 ◽  
Vol 22 (3) ◽  
pp. 1004
Author(s):  
Akira Sugiyama ◽  
Yurie Shimizu ◽  
Muneyoshi Okada ◽  
Kosuke Otani ◽  
Hideyuki Yamawaki
Keyword(s):  
Ventricular Arrhythmia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Glucose Deprivation ◽  
Clinical Problem ◽  
Neonatal Rat ◽  
Ros Production ◽  
Preventive Effect ◽  
Rat Cardiomyocytes

Ventricular arrhythmia induced by ischemia/reperfusion (I/R) injury is a clinical problem in reperfusion therapies for acute myocardial infarction. Ca2+ overload through reactive oxygen species (ROS) production is a major cause for I/R-induced arrhythmia. We previously demonstrated that canstatin, a C-terminal fragment of type IV collagen α2 chain, regulated Ca2+ handling in rat heart. In this study, we aimed to clarify the effects of canstatin on I/R-induced ventricular arrhythmia in rats. Male Wistar rats were subjected to I/R injury by ligating the left anterior descending artery followed by reperfusion. Ventricular arrhythmia (ventricular tachycardia and ventricular fibrillation) was recorded by electrocardiogram. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and ROS production in neonatal rat cardiomyocytes (NRCMs) stimulated with oxygen glucose deprivation/reperfusion (OGD/R) were measured by lucigenin assay and 2′,7′-dichlorodihydrofluorescein diacetate staining, respectively. The H2O2-induced intracellular Ca2+ ([Ca2+]i) rise in NRCMs was measured by a fluorescent Ca2+ indicator. Canstatin (20 µg/kg) inhibited I/R-induced ventricular arrhythmia in rats. Canstatin (250 ng/mL) inhibited OGD/R-induced NOX activation and ROS production and suppressed the H2O2-induced [Ca2+]i rise in NRCMs. We for the first time demonstrated that canstatin exerts a preventive effect against I/R-induced ventricular arrhythmia, perhaps in part through the suppression of ROS production and the subsequent [Ca2+]i rise.

Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats

Pharmacology ◽  
2021 ◽  
Vol 106 (3-4) ◽  
pp. 189-201
Author(s):  
Shigang Qiao ◽  
Wen-jie Zhao ◽  
Huan-qiu Li ◽  
Gui-zhen Ao ◽  
Jian-zhong An ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Neonatal Rat ◽  
Ligand Docking ◽  
Autophagic Flux ◽  
Myocardial Infarct Size ◽  
Rat Cardiomyocytes

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

scholarly journals Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 923
Author(s):  
Yuan Yuan ◽  
Yanyu Zhai ◽  
Jingjiong Chen ◽  
Xiaofeng Xu ◽  
Hongmei Wang
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Antioxidant Capacity ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Related Factor ◽  
Protective Effects

Kaempferol has been shown to protect cells against cerebral ischemia/reperfusion injury through inhibition of apoptosis. In the present study, we sought to investigate whether ferroptosis is involved in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal injury and the effects of kaempferol on ferroptosis in OGD/R-treated neurons. Western blot, immunofluorescence, and transmission electron microscopy were used to analyze ferroptosis, whereas cell death was detected using lactate dehydrogenase (LDH) release. We found that OGD/R attenuated SLC7A11 and glutathione peroxidase 4 (GPX4) levels as well as decreased endogenous antioxidants including nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and superoxide dismutase (SOD) in neurons. Notably, OGD/R enhanced the accumulation of lipid peroxidation, leading to the induction of ferroptosis in neurons. However, kaempferol activated nuclear factor-E2-related factor 2 (Nrf2)/SLC7A11/GPX4 signaling, augmented antioxidant capacity, and suppressed the accumulation of lipid peroxidation in OGD/R-treated neurons. Furthermore, kaempferol significantly reversed OGD/R-induced ferroptosis. Nevertheless, inhibition of Nrf2 by ML385 blocked the protective effects of kaempferol on antioxidant capacity, lipid peroxidation, and ferroptosis in OGD/R-treated neurons. These results suggest that ferroptosis may be a significant cause of cell death associated with OGD/R. Kaempferol provides protection from OGD/R-induced ferroptosis partly by activating Nrf2/SLC7A11/GPX4 signaling pathway.

Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium Against Ischemia-Reperfusion Injury in Canis

Hypertension ◽  
2021 ◽  
Vol 78 (5) ◽  
pp. 1541-1554
Author(s):  
Hongyun Wang ◽  
Rusitanmujiang Maimaitiaili ◽  
Jianhua Yao ◽  
Yuling Xie ◽  
Sujing Qiang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Human Embryonic Stem Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Embryonic Stem ◽  
Cardiomyocyte Apoptosis ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes

Plasma circulating extracellular vesicles (EVs) have been utilized as a potential therapeutic strategy to treat ischemic disease through intramyocardial injection (efficient but invasive) or tail vein injection (noninvasive but low cardiac retention). An effective and noninvasive delivery of EVs for future clinical use is necessary. The large animal (canine) model was complemented with a murine ischemia-reperfusion injury (IRI) model, as well as H9 human embryonic stem cell–induced cardiomyocytes or neonatal rat cardiomyocytes to investigate the effective delivery method and the role of plasma EVs in the IRI model. We further determine the crucial molecule within EVs that confers the cardioprotective role in vivo and in vitro and investigate the efficiency of CHP (cardiac homing peptide)-linked EVs in alleviating IRI. D-SPECT imaging showed that percutaneous intracoronary delivery of EVs reduced infarct extent in dogs. CHP-EVs further reduced IRI-induced cardiomyocyte apoptosis in mice and neonatal rat cardiomyocytes. Mechanistically, administration of EVs by percutaneous intracoronary delivery (in dog) and myocardial injection (in mice) just before reperfusion reduced infarct size of IRI by increasing miR-486 levels. miR-486–deleted EVs exacerbated oxygen-glucose deprivation/reoxygenation–induced human embryonic stem cell–induced cardiomyocytes and neonatal rat cardiomyocyte apoptosis. EV-miR-486 inhibited the PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression and then promoted AKT (protein kinase B) activation in human embryonic stem cell–induced cardiomyocytes and neonatal rat cardiomyocytes. In conclusion, plasma-derived EVs convey miR-486 to the myocardium and attenuated IRI-induced infarction and cardiomyocyte apoptosis. CHP strategy was effective to improve cardiac retention of EVs in mice (in vivo) and dogs (ex vivo).

scholarly journals Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway

2017 ◽  
Vol 44 (3) ◽  
pp. 1011-1023 ◽  
Author(s):  
Hui Liu ◽  
Xibo Jing ◽  
Aiqiao Dong ◽  
Baobao Bai ◽  
Haiyan Wang
Keyword(s):  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Ros Production ◽  
Rat Cardiomyocytes ◽  
Doxorubicin Treatment ◽  
Myocardial Apoptosis

Background/Aims: Myocardial ischemia/reperfusion (I/R) injury remains a great challenge in clinical therapy. Tissue inhibitor of metalloproteinases 3 (TIMP3) plays a crucial role in heart physiological and pathophysiological processes. However, the effects of TIMP3 on I/R injury remain unknown. Methods: C57BL/6 mice were infected with TIMP3 adenovirus by local delivery in myocardium followed by I/R operation or doxorubicin treatment. Neonatal rat cardiomyocytes were pretreated with TIMP3 adenovirus prior to anoxia/reoxygenation (A/R) treatment in vitro. Histology, echocardiography, in vivo phenotypical analysis, flow cytometry and western blotting were used to investigate the altered cardiac function and underlying mechanisms. Results: The results showed that upregulation of TIMP3 in myocardium markedly inhibited myocardial infarct areas and the cardiac dysfunction induced by I/R or by doxorubicin treatment. TUNEL staining revealed that TIMP3 overexpression attenuated I/R-induced myocardial apoptosis, accompanied by decreased Bax/Bcl-2 ratio, Cleaved Caspase-3 and Cleaved Caspase-9 expression. In vitro, A/R-induced cardiomyocyte apoptosis was abrogated by pharmacological inhibition of reactive oxygen species (ROS) production or MAPKs signaling. Attenuation of ROS production reversed A/R-induced MAPKs activation, whereas MAPKs inhibitors showed on effect on ROS production. Furthermore, in vivo or in vitro overexpression of TIMP3 significantly inhibited I/R- or A/R-induced ROS production and MAPKs activation. Conclusion: Our findings demonstrate that TIMP3 upregulation protects against cardiac I/R injury through inhibiting myocardial apoptosis. The mechanism may be related to inhibition of ROS-initiated MAPKs pathway. This study suggests that TIMP3 may be a potential therapeutic target for the treatment of I/R injury.

Abstract 354: Prostaglandin D 2 -F Type Prostanoid Receptor Signaling Is a Novel Cardiomyocyte Survival Pathway

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yoshinori Katsumata ◽  
Motoaki Sano ◽  
Tomohiro Matsuhashi ◽  
Atsushi Anzai ◽  
Cardex Yan ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Expression Profiles ◽  
Ischemia Reperfusion ◽  
Cardioprotective Effect ◽  
Neonatal Rat ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Rat Cardiomyocytes ◽  
Fp Receptor

Background: Lipocalin-type prostaglandin D synthase (L-PGDS) is abundantly expressed on cardiomyocytes. We recently demonstrated that dexamethasone stimulates PGD 2 -dominated activation of prostanoid biosynthesis, thereby protecting hearts against ischemia/reperfusion injury. Here, we examined the downstream signaling responsible for cardioprotection mediated through PGD 2 -dominated activation. Methods and Results: (1) In cultured neonatal rat cardiomyocytes, PGD 2 strongly activates ERK in a dose-dependent manner, although canonical PGD 2 receptors, including DP (PGD 2 receptor) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptors, are hardly expressed on cardiomyocytes. (2) Interestingly, PGD 2 bounds to FP receptor (the canonical PGF 2 α receptor) with an affinity comparable to that for the DP receptor, and the FP receptor is abundantly expressed on cardiomyocytes. (3) PGD 2 -induced ERK activation is completely blocked by FP antagonist or siRNA-mediated knockdown of the FP, but not by DP and CRTH2 antagonist and siRNA-mediated knockdown of DP and CRTH2. (4) PGD 2 activates ERK in Langendorff perfused DP-knock out (KO) and CRTH2-KO mice hearts to comparable levels as those observed for wild-type hearts, while cannot activate it in FP-KO hearts. (5) Consistently, the cardioprotective effect of PGD 2 -dominated activation by dexamethasone was blunted in FP KO hearts. (6) Furtermore, genomewide gene expression profiles by microarray analysis and quantitative real-time RT-PCR analysis identified that Nrf-2 was the downstream target of L-PGDS-mediated PGD 2 biosynthesis. (7) In cultured cardiomyocytes, FP agonist stimulated Nrf2 nuclear translocation and consequently induced Nrf2-target genes expression in an ERK-dependent manner. (8) Finally, The cardioprotective effect by dexamethasone was completely abolished in Nrf-2 KO hearts. Conclusion: FP serves as a functionally relevant PGD 2 receptor in the hearts and PGD 2 -FP signaling plays a substantial role in the improvement of functional recovery after ischemia-reperfusion injury in the heart. Nrf-2 is a major effector molecule responsible for the cardioprotecton elicited by L-PGDS-derived PGD 2 .

scholarly journals Initiation and propagation of ectopic waves: insights from an in vitro model of ischemia-reperfusion injury

2002 ◽  
Vol 283 (2) ◽  
pp. H741-H749 ◽  
Author(s):  
Ara Arutunyan ◽  
Luther M. Swift ◽  
Narine Sarvazyan
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Border Zone ◽  
Ectopic Activity ◽  
Functional Layer ◽  
Rat Cardiomyocytes ◽  
Coupled Cells ◽  
Vitro Model

The objective of the present study was to directly visualize ectopic activity associated with ischemia-reperfusion and its progression to arrhythmia. To accomplish this goal, we employed a two-dimensional network of neonatal rat cardiomyocytes and a recently developed model of localized ischemia-reperfusion. Washout of the ischemia-like solution resulted in tachyarrhythmic episodes lasting 15–200 s. These episodes were preceded by the appearance of multiple ectopic sources and propagation of ectopic activity along the border of the former ischemic zone. The ectopic sources exhibited a slow rise in diastolic calcium, which disappeared upon return to the original pacing pattern. Border zone propagation of ectopic activity was followed by its escape into the surrounding control network, generating arrhythmias. Together, these observations suggest that upon reperfusion, a distinct layer, which consists of ectopically active, poorly coupled cells, is formed transiently over an injured area. Despite being neighbored by a conductive and excitable tissue, this transient functional layer is capable of sustaining autonomous waves and serving as a special conductive medium through which ectopic activity can propagate before spreading into the surrounding healthy tissue.

Radicicol activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes

2004 ◽  
Vol 287 (3) ◽  
pp. H1081-H1088 ◽  
Author(s):  
Tina M. Griffin ◽  
Tina V. Valdez ◽  
Ruben Mestril
Keyword(s):  
Heat Shock ◽  
Transcriptional Activation ◽  
Cardiac Tissue ◽  
Defense Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Heat Shock Factor 1 ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes

Heat shock proteins (HSPs) constitute an endogenous cellular defense mechanism against environmental stresses. In the past few years, studies have shown that overexpression of HSPs can protect cardiac myocytes against ischemia-reperfusion injury. In an attempt to increase the HSPs in cardiac tissue, we used the compound radicicol that activates HSP expression by binding to the HSP 90 kDa (HSP90). HSP90 is the main component of the cytosolic molecular chaperone complex, which has been implicated in the regulation of the heat shock factor 1 (HSF1). HSF1 is responsible for the transcriptional activation of the heat shock genes. In the present study, we show that radicicol induces HSP expression in neonatal rat cardiomyocytes, and this increase in HSPs confers cardioprotection to these cardiomyocytes. We also show that radicicol induction of the HSP and cardioprotection is dependent on the inhibition of HSP90 in cardiomyocytes. These results indicate that modulation of the active HSP90 protein level plays an important role in cardioprotection. Therefore, compounds, such as radicicol and its possible derivatives that inhibit the function of HSP90 in the cell may represent potentially useful cardioprotective agents.

Hydroperoxide-induced oxidative stress impairs heart muscle cell carbohydrate metabolism

1994 ◽  
Vol 266 (1) ◽  
pp. C179-C188 ◽  
Author(s):  
D. R. Janero ◽  
D. Hreniuk ◽  
H. M. Sharif
Keyword(s):  
Oxidative Stress ◽  
Carbohydrate Metabolism ◽  
Heart Muscle ◽  
Ischemia Reperfusion Injury ◽  
Tricarboxylic Acid Cycle ◽  
Ischemia Reperfusion ◽  
Alpha Tocopherol ◽  
Neonatal Rat ◽  
Glycolytic Flux ◽  
Rat Cardiomyocytes

Hydrogen peroxide (H2O2) may incite cardiac ischemia-reperfusion injury. We evaluate herein the influence of H2O2-induced oxidative stress on heart muscle hexose metabolism in cultured neonatal rat cardiomyocytes, which have a substrate preference for carbohydrate. Cardiomyocyte exposure to 50 microM-1.0 mM bolus H2O2 transiently activated the pentose phosphate cycle and thereafter inhibited cellular glucose oxidation and glycolysis. These metabolic derangements were nonperoxidative in nature (as assessed in alpha-tocopherol-loaded cells) and occurred without acute change in cardiomyocyte hexose transport or glucose/glycogen reserves. Glycolytic inhibition was supported by the rapid, specific inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The degree of GAPDH inhibition correlated directly with the magnitude of the oxidative insult and was independent of both metal-catalyzed H2O2 reduction to free radicals and lipid peroxidation. Severe GAPDH inhibition was required for a rate-limiting effect on glycolytic flux. Cardiomyocyte pyruvate dehydrogenase was also inhibited by H2O2 overload, but to a lesser degree than GAPDH such that entry of hexose-derived acetyl units into the tricarboxylic acid cycle was not as restrictive as GAPDH inactivation to glycolytic ATP production. An increase in phosphofructokinase activity accompanied GAPDH inactivation, leading to the production and accumulation of glycolytic sugar phosphates at the expense of ATP equivalents. Cardiomyocyte treatment with iodoacetate or 2-deoxyglucose indicated that GAPDH inactivation/glycolytic blockade could account for approximately 50% of the maximal ATP loss following H2O2 overload. Partial restoration of GAPDH activity after a brief H2O2 "pulse" afforded some ATP recovery. These data establish that specific aspects of heart muscle hexose catabolism are H2O2-sensitive injury targets. The biochemical pathology of H2O2 overload on cardiomyocyte carbohydrate metabolism has implications for post-ischemic cardiac bioenergetics and function.

scholarly journals RRM2 Improves Cardiomyocyte Proliferation after Myocardial Ischemia Reperfusion Injury through the Hippo-YAP Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Huamin Yu ◽  
Haiyan Tang ◽  
Chaochao Deng ◽  
Qing Lin ◽  
Peng Yu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Cell Counting ◽  
Cardiomyocyte Proliferation ◽  
Rat Cardiomyocytes ◽  
Qrt Pcr ◽  
Myocardial Ischemia Reperfusion ◽  
Deoxyribonucleoside Triphosphate

Objective. Ribonucleotide reductase M2 (RRM2) as an enzyme that catalyzes the deoxyreduction of nucleosides to deoxyribonucleoside triphosphate (dNTP) has been extensively studied, and it plays a crucial role in regulating cell proliferation. However, its role in ischemia-reperfusion injury (I/RI) is still unclear. Methods. SD rats were used as the research object to detect the expression of RRM2 in the myocardium by constructing an I/RI model. At the same time, primary SD neonatal rat cardiomyocytes were extracted, and hypoxia/reoxygenation (H/R) treatment simulated the I/RI model. Using transfection technology to overexpress RRM2 in cardiomyocytes, quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of RRM2, Cell Counting Kit-8 (CCK-8) assay was used to detect cell viability, and immunofluorescence staining was used to detect Ki67 and EdU-positive cells. Western blot (WB) technology was used to detect YAP and its phosphorylation expression. Results. qRT-PCR results indicated that the expression of RRM2 was inhibited in the model group, and cardiomyocytes overexpressing RRM2 can obviously promote the proliferation of primary cardiomyocytes and improve the damage of cardiac structure and function caused by I/R. At the same time, RRM2 can promote the increase of YAP protein expression and the increase of Cyclin D1 mRNA expression. Conclusion. RRM2 expression was downregulated in myocardial tissue with I/R. After overexpression of RRM2, cardiomyocyte proliferation was upregulated and the Hippo-YAP signaling pathway was activated.

Abstract 258: Nanoparticle-mediated Targeting of a Chemical Inhibitor of Drp1 to the Mitochondria Induces Cardioprotection From Myocardial Ischemia-reperfusion Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ayako Ishikita ◽  
Tetusya Matoba ◽  
Gentaro Ikeda ◽  
Kensuke Egashira
Keyword(s):  
Cyclosporine A ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Plga Nanoparticles ◽  
Neonatal Rat ◽  
Poly Lactic Acid ◽  
Cyclophilin D ◽  
Rat Cardiomyocytes ◽  
Mptp Opening

Background: Mitochondria (MITO) injury including MITO permeability transition pore (mPTP) opening plays a major role in the mechanism of ischemia-reperfusion (IR) injury. Intravenous administration of an inhibitor of mPTP opening, cyclosporine A, can reduce IR injury in animals and patients with acute myocardial infarction (MI), however; the power of cardioprotection by cyclosporine A is insufficient. We tested the hypothesis that nanoparticle-mediated targeting of Mdivi1, a chemical inhibitor of Drp1, to MITO enhances cardioprotection from IR injury. Methods and Results: We formulated poly(lactic acid/glycolic acid) (PLGA) nanoparticles containing Mdivi1 (Mdivi1-NP) or FITC (FITC-NP). In neonatal rat cardiomyocytes, PLGA nanoparticles accumulated in MITO after the addition of hydrogen peroxide (H2O2) that represents oxidative stress during IR (Fig.A). Treatment with Mdivi1-NP reduced H2O2-induced MITO division and cardiomyocyte death (Fig.B). This Mdivi1-NP cardioprotective effect was not seen over adenovirus harboring Drp1 shRNA transduced cardiomyocyte. In an in vivo and ex vivo murine model, treatment with Mdivi1-NP at the time of reperfusion reduced infarct size more effectively than Mdivi1 alone (Fig.C). Interestingly, Mdivi1-NP inhibited the leakage of cytochrome c to cytosol and MITO swelling, and reduced IR injury in both wildtype and cyclophilin D (a key regulatory molecule for mPTP opening)-KO mice (Fig.D). Conclusions: Mdivi1-NP enhanced cardioprotection against IR injury through mechanisms independent of mPTP opening. Mdivi1-NP can be a novel cardioprotective strategy in acute MI.

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