scholarly journals Sarcopenia-derived exosomal micro-RNA 16-5p disturbs cardio-repair via a pro-apoptotic mechanism in myocardial infarction in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Taiki Hayasaka ◽  
Naofumi Takehara ◽  
Tatsuya Aonuma ◽  
Kohei Kano ◽  
Kiwamu Horiuchi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Myocytes ◽  
Underlying Mechanism ◽  
Cardiac Repair ◽  
Micro Rna ◽  
Neonatal Rat ◽  
Skeletal Muscle Atrophy ◽  
Cardiac Cachexia ◽  
Hypoxic Conditions

AbstractSarcopenia is a pathophysiological malfunction induced by skeletal muscle atrophy. Several studies reported an association between sarcopenia-induced cardiac cachexia and poor prognosis in heart disease. However, due to lack of an established animal models, the underlying mechanism of disturbed cardiac repair accompanied with sarcopenia remains poorly understood. Here, we developed a novel sarcopenia-induced cardiac repair disturbance mouse model induced by tail suspension (TS) after cardiac ischemia and reperfusion (I/R). Importantly, we identified a specific exosomal-microRNA marker, miR-16-5p, in the circulating exosomes of I/R-TS mice. Of note, sarcopenia after I/R disturbed cardiac repair and raised the level of circulating-exosomal-miR-16-5p secreting from both the atrophic limbs and heart of TS mice. Likewise, miR-16-5p mimic plasmid disturbed cardiac repair in I/R mice directly. Additionally, in neonatal rat ventricular myocytes (NRVMs) cultured in vitro under hypoxic conditions in the presence of a miR-16-5p mimic, we observed increased apoptosis through p53 and Caspase3 upregulation, and also clarified that autophagosomes were decreased in NRVMs via SESN1 transcript interference-mediated mTOR activation. In conclusion, we show the pro-apoptotic effect of sarcopenia-derived miR-16-5p, which may be behind the exacerbation of myocardial infarction. Therefore, miR-16-5p can be a novel therapeutic target in the context of cardiac repair disturbances in sarcopenia–cachexia.

scholarly journals METTL3 improves cardiomyocyte proliferation upon myocardial infarction via upregulating miR-17-3p in a DGCR8-dependent manner

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kun Zhao ◽  
Chuanxi Yang ◽  
Jing Zhang ◽  
Wei Sun ◽  
Bin Zhou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Rna Binding ◽  
Underlying Mechanism ◽  
Neonatal Rat ◽  
Dependent Manner ◽  
Cardiomyocyte Proliferation ◽  
Rat Cardiomyocytes

AbstractMyocardial infarction (MI), one of the most severe types of heart attack, exerts a strong negative effect on heart muscle by causing a massive and rapid loss of cardiomyocytes. However, the existing therapies do little to improve cardiac regeneration. Due to the role of methyltransferase-like 3 (METTL3) in the physiological proliferation of cardiomyocytes, we aimed to determine whether METTL3 could also promote cardiomyocyte proliferation under pathological conditions and to elucidate the underlying mechanism. The effects of METTL3 on cardiomyocyte proliferation and apoptosis were investigated in an in vivo rat model of MI and in an in vitro model of neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia. We found that METTL3 expression was downregulated in hypoxia-exposed NRCMs and MI-induced rats. Furthermore, METTL3 pretreatment enhanced cardiomyocyte proliferation and inhibited cardiomyocyte apoptosis under hypoxic or MI conditions, and silencing METTL3 had the opposite effects. Additionally, METTL3 overexpression upregulated miR-17-3p expression. The miR-17-3p agomir mimicked the pro-proliferative and antiapoptotic effects of METTL3 in hypoxia-exposed cells or rats with MI, while the miR-17-3p antagomir blocked these effects. Additionally, pretreatment with the RNA-binding protein DGCR8 also hampered the protective role of METTL3 in hypoxia-exposed cells. Overall, the current study indicated that METTL3 could improve cardiomyocyte proliferation and subsequently ameliorate MI in rats by upregulating proliferation-related miR-17-3p in a DGCR8-dependent pri-miRNA-processing manner.

Abstract 9: Temperature-responsive Cell Delivery Biopolymers for Cardiac Tissue Engineering

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Brisa Pena ◽  
Valentina Martinelli ◽  
Susanna Bosi ◽  
Carmen Sucharov ◽  
Mark Jeong ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Body Temperature ◽  
Cell Viability ◽  
Cultured Cells ◽  
Ventricular Myocytes ◽  
3D Culture ◽  
Polymeric Matrix ◽  
Neonatal Rat ◽  
Cell Delivery

Background: Advances in cell therapy and material science have made tissue engineering a promising strategy for heart regeneration. We developed an injectable biomimetic reverse thermal gel (RTG) that is liquid at room temperature but gel-like at body temperature, with the ultimate goal of being able to serve as a vehicle for cell-based delivery (liquid) to targeted tissue areas (gel-phase at 37°C). In this study we tested the suitability of this biomimetic RTG on cell viability. Methods and results: We tested different biomimetic RTG systems with and without the chemical incorporation of lysine. In vitro 3D culture experiments were performed with neonatal rat ventricular myocytes (NRVM) by mixing 3x104 cells with 50 μl of polymeric solution and allowing gel formation at 37°C. The cultured cells were incubated for 21 days. For controls we used NRVMs plated on 2D traditional gelatin coated dishes. We found that the 3D polymeric matrix induces rapid coordinated contraction with improved functionality when compared with standard 2D-cultured NRVM. By immunostaining for the morphology of the sarcomere (alpha-actinin) and DAPI, we also observed that the 3D polymeric matrix stimulates cells to spread and form 3D syncytia. Conclusion: These proof-of-concept results demonstrate long-term cell viability in this unique biomimetic system and therefore provide feasibility of a polymeric cell delivery system that permits reversible liquid-to-gel transition at body temperature. These results offer potential for a tissue engineering approach to cardiac regeneration.

Abstract 259: KChIP2 is a Key Transcriptional Regulator of Cardiac Excitability Under Normal and Pathogenic Conditions

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Drew M Nassal ◽  
Xiaoping Wan ◽  
Haiyan Liu ◽  
Danielle Maleski ◽  
Angelina Ramirez-Navarro ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ventricular Myocytes ◽  
Direct Interaction ◽  
Neonatal Rat ◽  
K Channel ◽  
Early Event ◽  
Interacting Protein ◽  
Protein Levels ◽  
Cardiac Excitability

Introduction: Arrhythmogenesis is the primary cause of death in patients with acquired heart disease, and is the consequence of profound dysregulation of both depolarizing and repolarizing currents. Reduction in expression of the auxiliary subunit K+ channel interacting protein 2 (KChIP2), which regulates the transient outward K+ current (Ito), is a common and early event in many cardiac pathologies. Notably, transcriptional changes observed in heart disease can be elicited through direct KChIP2 silencing without disease signaling, suggesting novel transcriptional capacity for KChIP2. Methods and Results: A miRNA microarray was conducted on neonatal rat ventricular myocytes (NRVM) following in vitro silencing of KChIP2, identifying the miR-34 family as a potential transcriptional target of KChIP2. qPCR confirmed reduction in miR-34b/c when over-expressing KChIP2 and increase following silencing. Luciferase assays conducted on the promoter for miR-34b/c reinforced KChIP2 repression on the promoter, while chromatin immunoprecipitation identified direct interaction of KChIP2 on the promoter. Previous studies show modified expression of KChIP2 can lead to changes in several ion channel subunits. Therefore, we investigated if this was the consequence of KChIP2 regulation via miR-34. Expression of miR-34b/c precursors reduced transcript levels of Nav1.5 and Navβ1, and reduced protein levels for Kv4.3, resulting in loss of INa and Ito. To determine the relevance in disease signaling, NRVMs were exposed to 100 μM phenylephrine for 48 hrs, significantly reducing KChIP2, Nav1.5, Navβ1, and Kv4.3, while elevating miR-34b/c. Maintaining KChIP2 expression by adenovirus or blocking miR-34 activity with antagomirs rescued the changes in channel expression. Consequently, miR-34 inhibition rescued the induction of sustained arrhythmias observed in a 2D culture of myocytes through the maintenance of cardiac excitability. Conclusion: Collectively, these observations identify dysregulation of the KChIP2/miR-34 axis as a nodal event in the development of electrical dysfunction that characterize cardiac pathologies, and further identifies miR-34 as a viable therapeutic target for managing arrhythmogenesis in patients with heart disease.

Abstract 631 ADAM12 Is An Important Regulator Of Myocyte Apoptosis Induced By β-adrenergic Receptor Stimulation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hang Xi ◽  
Khadija Rafiq ◽  
Marie Hanscom ◽  
Rachid Seqqat ◽  
Nikolay L Malinin ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Surface Proteins ◽  
Neonatal Rat ◽  
Human Heart Failure ◽  
Activation Mechanisms ◽  
Myocyte Apoptosis ◽  
Protease Deficient

ADAM (A Disintegrin And Metalloprotease)12 is a member of a family of cell surface proteins with protease and cell-binding activities. Recent work showed ADAM12 up-regulation in human heart failure. However, the activation mechanisms of ADAM12 in the heart are obscure. We hypothesized that β-adrenergic receptors (AR) stimulation regulates ADAM12 activation in neonatal rat ventricular myocytes (NRVMs) in-vitro and after injection of isoproterenol (ISO) in-vivo. Wistar rats received a single injection of ISO (5 mg/kg) and were sacrificed 6, 24 and 72 hrs later. In comparison with controls, left ventricular function was impaired in rats 24 hrs after ISO injection and started to improve at 72 hrs. The fraction of myocytes undergoing apoptosis peaked 24 hrs after ISO injection and declined thereafter. ADAM12 protein was reduced in hearts from ISO treated animals at 6 hrs, pointing to a possible increase in ADAM12 proteolytic activity. However, both ADAM12 expression and activation were significantly up-regulated at 24 and 72 hrs after ISO injection. We therefore assessed whether ADAM12 activation was involved in myocyte apoptosis secondary to excess exposure of catecholamine. Acute stimulation with ISO (10 μM, 30 min to 3 hrs) induced accumulation of ADAM12 N-terminal cleavage product in conditioned medium, demonstrating activation of the ADAM metalloprotease activity. However, chronic stimulation with ISO for 24 hrs and 48 hrs significantly increased both ADAM12 expression and secretion. This ISO-induced ADAM12 expression/activation was mediated through β 1 -AR stimulation and was dependent on intracellular calcium elevation and protein kinase C activation. Adenoviral expression of an ADAM12 protease-deficient mutant (ADAM12DeltaMP) blocks β-AR-induced myocyte apoptosis, while transduction of NRVMs with adenovirus harboring ADAM12 significantly increased myocyte apoptosis. These data suggest that ADAM12 is a regulator of myocyte apoptosis induced by β-AR in NRVMs and may play an important autocrine role in mediating the effects of β-AR on myocardial remodeling.

Abstract 356: KChIP2 Mediates Ion Channel Dysregulation by Novel Transcriptional Regulation of miR-34s

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Drew Nassal ◽  
Haiyan Liu ◽  
Xiaoping Wan ◽  
Angelina Ramirez-Navarro ◽  
Eckhard Ficker ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ion Channel ◽  
Transcriptional Control ◽  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Physical Interaction ◽  
Protein Patterns ◽  
Protein Levels ◽  
Disease States

Introduction: Cardiac ion channel dysregulation is a hallmark of heart failure. Consistently, the disease yields dramatic decline in Ito through loss in Kv4 and its auxiliary partner KChIP2. Notably, transcriptional changes in heart failure can be elicited through KChIP2 silencing without disease signaling, suggesting potential transcriptional capacity for KChIP2. Further, disparity between resulting transcript and protein patterns suggests a mechanism compatible with modified miRNA activity. Considering other members of the KChIP family behave as transcriptional repressors, we hypothesize that KChIP2 regulates discrete miRNAs which in turn regulate cardiac excitability. Methods and Results: A miRNA microarray was conducted on neonatal rat ventricular myocytes (NRVM) following in vitro silencing of KChIP2 by siRNA, identifying the miR-34 family as potential transcriptional targets of KChIP2. Regulation, confirmed by quantitative PCR, showed reduction in miR-34a/b/c when over-expressing KChIP2 and increase following silencing. Luciferase assays were performed on the cloned promoter for miR-34b/c which reinforced direct KChIP2 repression on the miR-34b/c promoter. Furthermore, chromatin immunoprecipitation followed by PCR identified physical interaction of KChIP2 to the promoter site. Previous studies show modified expression of KChIP2 can lead to changes in several ion channel subunits. Therefore, we investigated if this was the consequence of KChIP2 regulation via miR-34. miR-34a/b/c precursors were expressed in NRVM which reduced transcript levels of Nav1.5 and Navβ1, and reduced protein levels for Kv4.3. Reflecting these changes, peak INa was reduced following miR precursor treatment. NRVMs were exposed to 100 μM phenylephrine for 48 hrs, significantly reducing KChIP2, Nav1.5, Navβ1, and Kv4.3, while elevating miR-34b/c. Returning KChIP2 expression by adenovirus normalized these changes back towards baseline, implicating the physiologic relevance of this pathway. Conclusion: These observations describe a novel mechanism where KChIP2 regulates a host of cardiac genes through transcriptional control of miRNAs, potentially explaining electrical remodeling observed in disease states where KChIP2 is reduced.

scholarly journals Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Tae-Jun Park ◽  
Jei Hyoung Park ◽  
Ga Seul Lee ◽  
Ji-Yoon Lee ◽  
Ji Hye Shin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Lipid Peroxide ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Myocardial Cell ◽  
Gene Set Enrichment Analysis ◽  
Neonatal Rat ◽  
Transcriptional Level ◽  
Regulated Necrosis

Abstract Ischaemic heart disease (IHD) is the leading cause of death worldwide. Although myocardial cell death plays a significant role in myocardial infarction (MI), its underlying mechanism remains to be elucidated. To understand the progression of MI and identify potential therapeutic targets, we performed tandem mass tag (TMT)-based quantitative proteomic analysis using an MI mouse model. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) revealed that the glutathione metabolic pathway and reactive oxygen species (ROS) pathway were significantly downregulated during MI. In particular, glutathione peroxidase 4 (GPX4), which protects cells from ferroptosis (an iron-dependent programme of regulated necrosis), was downregulated in the early and middle stages of MI. RNA-seq and qRT-PCR analyses suggested that GPX4 downregulation occurred at the transcriptional level. Depletion or inhibition of GPX4 using specific siRNA or the chemical inhibitor RSL3, respectively, resulted in the accumulation of lipid peroxide, leading to cell death by ferroptosis in H9c2 cardiomyoblasts. Although neonatal rat ventricular myocytes (NRVMs) were less sensitive to GPX4 inhibition than H9c2 cells, NRVMs rapidly underwent ferroptosis in response to GPX4 inhibition under cysteine deprivation. Our study suggests that downregulation of GPX4 during MI contributes to ferroptotic cell death in cardiomyocytes upon metabolic stress such as cysteine deprivation.

scholarly journals Grape Seed Proanthocyanidin Extract Ameliorates Cardiac Remodelling After Myocardial Infarction Through PI3K/AKT Pathway in Mice

2020 ◽  
Vol 11 ◽  
Author(s):  
Yongxue Ruan ◽  
Qike Jin ◽  
Jingjing Zeng ◽  
Fangfang Ren ◽  
Zuoyi Xie ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Grape Seed ◽  
Akt Pathway ◽  
Grape Seeds ◽  
Hypoxic Conditions ◽  
Grape Seed Proanthocyanidin Extract ◽  
Grape Seed Proanthocyanidin

Myocardial infarction is one of the most serious fatal diseases in the world, which is due to acute occlusion of coronary arteries. Grape seed proanthocyanidin extract (GSPE) is an active compound extracted from grape seeds that has anti-oxidative, anti-inflammatory and anti-tumor pharmacological effects. Natural products are cheap, easy to obtain, widely used and effective. It has been used to treat numerous diseases, such as cancer, brain injury and diabetes complications. However, there are limited studies on its role and associated mechanisms in myocardial infarction in mice. This study showed that GSPE treatment in mice significantly reduced cardiac dysfunction and improved the pathological changes due to MI injury. In vitro, GSPE inhibited the apoptosis of H9C2 cells after hypoxia culture, resulting in the expression of Bax decreased and the expression of Bcl-2 increased. The high expression of p-PI3K and p-AKT was detected in MI model in vivo and in vitro. The use of the specific PI3K/AKT pathway inhibitor LY294002 regressed the cardio-protection of GSPE. Our results showed that GSPE could improve the cardiac dysfunction and remodeling induced by MI and inhibit cardiomyocytes apoptosis in hypoxic conditions through the PI3K/AKT signaling pathway.

scholarly journals Cardiomyocyte functional screening: interrogating comparative electrophysiology of high-throughput model cell systems

2019 ◽  
Vol 317 (6) ◽  
pp. C1256-C1267 ◽  
Author(s):  
Simon P. Wells ◽  
Helen M. Waddell ◽  
Choon Boon Sim ◽  
Shiang Y. Lim ◽  
Gabriel B. Bernasochi ◽  
...  
Keyword(s):  
Conduction Velocity ◽  
High Throughput ◽  
Microelectrode Array ◽  
Ventricular Myocytes ◽  
Field Potential ◽  
Induced Pluripotent Stem Cell ◽  
Neonatal Rat ◽  
Functional Screening ◽  
Electrophysiological Properties

Cardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48–120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the β-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis.

Increased endothelin-1 and endothelin receptor expression in myocytes of ischemic and reperfused rat hearts and ventricular myocytes exposed to ischemic conditions and its inhibition by nitric oxide generation

2003 ◽  
Vol 81 (2) ◽  
pp. 105-113 ◽  
Author(s):  
Xiaohong Tracey Gan ◽  
Subrata Chakrabarti ◽  
Morris Karmazyn
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Ventricular Myocytes ◽  
Receptor Expression ◽  
Neonatal Rat ◽  
No Donor ◽  
Myocardial Ischemia And Reperfusion ◽  
Endothelin 1 ◽  
Hypoxic Conditions ◽  
Rat Hearts

Endothelin-1 (ET-1) and nitric oxide (NO) exert opposite effects in the cardiovascular system, and there is evidence that the NO counters the potential deleterious effects of ET-1. We investigated whether NO affects the increased mRNA expression of ET-1 and endothelin receptors induced by (i) 30 min of ischemia with or without 30 min reperfusion in myocytes from isolated rat hearts or (ii) ischemic conditions (acidosis or hypoxia) in cultured rat neonatal ventricular myocytes. Ischemia with or without reperfusion produced more than a twofold increase in mRNA expression of ET-1 as well as the ETAand ETBreceptor (P < 0.05), although these effects were completely blocked by the NO donor 3-morpholinosydnonimine (SIN-1; 1 μM). To assess the possible factors regulating ET expression, myocytes were exposed to acidosis (pH 6.8–6.2) or to hypoxic conditions in an anaerobic chamber for 24 h in the presence or absence of SIN-1. At all acidic pHs, ET-1 and ETAreceptor mRNA expression was significantly (P < 0.05) elevated approximately threefold, although the magnitude of elevation was independent of the degree of acidosis. These effects were completely prevented by SIN-1. ETBreceptor expression was unaffected by acidosis. Hypoxia increased ET-1 as well as ETAand ETBreceptor expression threefold (P < 0.05), although this was unaffected by SIN-1. Our results demonstrate that myocardial ischemia and reperfusion upregulate the ET system, which is inhibited by NO. Although increased expression of the ET system can be mimicked by both acidosis and hypoxia, only the effects of the former are NO sensitive. NO may serve an endogenous inhibitory factor which regulates the expression of the ET system under pathological conditions.Key words: ET-1, ET receptors, NO, neonatal rat ventricular myocytes, hypoxia, acidosis.

scholarly journals Oleuropein Protects Cardiomyocyte against Apoptosis via Activating the Reperfusion Injury Salvage Kinase Pathway In Vitro

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Qiming Zhao ◽  
Yinliang Bai ◽  
Caie Li ◽  
Kun Yang ◽  
Wansheng Wei ◽  
...  
Keyword(s):  
Cell Injury ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Cardioprotective Effect ◽  
Neonatal Rat ◽  
Dye Reduction ◽  
Cellular Apoptosis ◽  
Cyt C ◽  
Reperfusion Injury Salvage Kinase

Oleuropein, the main glycoside present in olives, has been reported to have cardioprotective effect, but the exact mechanism has not been clearly elucidated. This study attempted to clarify the cardioprotective effect of oleuropein against simulated ischemia/reperfusion- (SI/R-) induced cardiomyocyte injury in vitro and further explore the underlying mechanism. Here we confirmed that oleuropein reduced the cell injury in neonatal rat cardiomyocyte induced by SI/R evidenced by decreasing MTT dye reduction and LDH activity in the culture medium. Meanwhile, the compound also inhibited reactive oxygen species excessive generation and stabilized mitochondrial membrane potential after SI/R. The flow cytometry assessment results indicated the inhibition of cellular apoptosis with oleuropein treatment. Furthermore, western blot analysis showed that oleuropein attenuated the expression of Cyt-C, c-caspase-3, and c-caspase-9, increased the Bcl-2/Bax ratio, and enhanced the phosphorylation of ERK1/2 and Akt after SI/R. However, the phosphorylation enhancement was partially abolished in the presence of LY294002 (PI3K inhibitor) and U0126 (ERK inhibitor). All these findings indicate that oleuropein has the protective potential against SI/R-induced injury and its protective effect may be partly due to the attenuation of apoptosis via the activation of the PI3K/Akt and ERK1/2 signaling pathways.

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