Apelin-13 protects the heart against ischemia-reperfusion injury through inhibition of ER-dependent apoptotic pathways in a time-dependent fashion

2011 ◽  
Vol 301 (4) ◽  
pp. H1471-H1486 ◽  
Author(s):  
Jianping Tao ◽  
Wei Zhu ◽  
Yapeng Li ◽  
Ping Xin ◽  
Jing Li ◽  
...  
Keyword(s):  
Er Stress ◽  
Signaling Pathways ◽  
Time Course ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Erk Activation ◽  
Caspase 12 ◽  
Induced Apoptosis ◽  
Stress Dependent

Endoplasmic reticulum (ER) stress is activated during and contributes to ischemia-reperfusion (I/R) injury. Attenuation of ER stress-induced apoptosis protects the heart against I/R injury. Using apelin, a ligand used to activate the apelin APJ receptor, which is known to be cardioprotective, this study was designed to investigate 1) the time course of changes in I/R injury after ER stress; 2) whether apelin infusion protects the heart against I/R injury via modulation of ER stress-dependent apoptosis signaling pathways; and 3) how phosphatidylinositol 3-kinase (PI3K)/Akt, endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and ERK activation are involved in the protection offered by apelin treatment. The results showed that, using an in vivo rat I/R model induced by 30 min of ischemia followed by reperfusion, infarct size (IS) increased from 2 h of reperfusion (34.85 ± 2.14%) to 12 h of reperfusion (48.98 ± 3.35, P < 0.05), which was associated with an abrupt increase in ER stress-dependent apoptosis activation, as evidenced by increased CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and JNK activation (CHOP: 2.49-fold increase, caspase-12: 2.09-fold increase, and JNK: 3.38-fold increase, P < 0.05, respectively). Administration of apelin at 1 μg/kg not only completely abolished the activation of ER stress-induced apoptosis signaling pathways at 2 h of reperfusion but also significantly attenuated time-related changes at 24 h of reperfusion. Using pharmacological inhibition, we also demonstrated that PI3K/Akt, AMPK, and ERK activation were involved in the protection against I/R injury via inhibition of ER stress-dependent apoptosis activation. In contrast, although eNOS activation played a role in decreasing IS at 2 h of reperfusion, it failed to modify either IS or ER stress-induced apoptosis signaling pathways at 24 h after reperfusion.

Oxidative and ER stress-dependent ASK1 activation in steatotic hepatocytes and Kupffer cells sensitizes mice fatty liver to ischemia/reperfusion injury

2017 ◽  
Vol 112 ◽  
pp. 141-148 ◽  
Author(s):  
Chiara Imarisio ◽  
Elisa Alchera ◽  
Chandrashekar Bangalore Revanna ◽  
Guido Valente ◽  
Antonia Follenzi ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Kupffer Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Stress Dependent

Interleukin 35 protects cardiomyocytes following ischemia/reperfusion-induced apoptosis via activation of mitochondrial STAT3

2021 ◽  
Author(s):  
Fengyun Zhou ◽  
Ting Feng ◽  
Xiangqi Lu ◽  
Huicheng Wang ◽  
Yangping Chen ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Cytochrome C Release ◽  
Neonatal Cardiomyocytes ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Abstract Mitochondrial reactive oxygen species (mtROS)-induced apoptosis has been suggested to contribute to myocardial ischemia/reperfusion injury. Interleukin 35 (IL-35), a novel anti-inflammatory cytokine, has been shown to protect the myocardium and inhibit mtROS production. However, its effect on cardiomyocytes upon exposure to hypoxia/reoxygenation (H/R) damage has not yet been elucidated. The present study aimed to investigate the potential protective role and underlying mechanisms of IL-35 in H/R-induced mouse neonatal cardiomyocyte injury. Mouse neonatal cardiomyocytes were challenged to H/R in the presence of IL-35, and we found that IL-35 dose dependently promotes cell viability, diminishes mtROS, maintains mitochondrial membrane potential, and decreases the number of apoptotic cardiomyocytes. Meanwhile, IL-35 remarkably activates mitochondrial STAT3 (mitoSTAT3) signaling, inhibits cytochrome c release, and reduces apoptosis signaling. Furthermore, co-treatment of the cardiomyocytes with the STAT3 inhibitor AG490 abrogates the IL-35-induced cardioprotective effects. Our study identified the protective role of IL-35 in cardiomyocytes following H/R damage and revealed that IL-35 protects cardiomyocytes against mtROS-induced apoptosis through the mitoSTAT3 signaling pathway during H/R.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

Decline of contractility during ischemia-reperfusion injury: actin glutathionylation and its effect on allosteric interaction with tropomyosin

2006 ◽  
Vol 290 (3) ◽  
pp. C719-C727 ◽  
Author(s):  
Frank C. Chen ◽  
Ozgur Ogut
Keyword(s):  
Reperfusion Injury ◽  
Posttranslational Modifications ◽  
Actin Polymerization ◽  
Time Course ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Concentration ◽  
Cross Sectional ◽  
The Impact

The severity and duration of ischemia-reperfusion injury is hypothesized to play an important role in the ability of the heart subsequently to recover contractility. Permeabilized trabeculae were prepared from a rat model of ischemia-reperfusion injury to examine the impact on force generation. Compared with the control perfused condition, the maximum force (Fmax) per cross-sectional area and the rate of tension redevelopment of Ca2+-activated trabeculae fell by 71% and 44%, respectively, during ischemia despite the availability of a high concentration of ATP. The reduction in Fmax with ischemia was accompanied by a decline in fiber stiffness, implying a drop in the absolute number of attached cross bridges. However, the declines during ischemia were largely recovered after reperfusion, leading to the hypothesis that intrinsic, reversible posttranslational modifications to proteins of the contractile filaments occur during ischemia-reperfusion injury. Examination of thin-filament proteins from ischemic or ischemia-reperfused hearts did not reveal proteolysis of troponin I or T. However, actin was found to be glutathionylated with ischemia. Light-scattering experiments demonstrated that glutathionylated G-actin did not polymerize as efficiently as native G-actin. Although tropomyosin accelerated the time course of native and glutathionylated G-actin polymerization, the polymerization of glutathionylated G-actin still lagged native G-actin at all concentrations of tropomyosin tested. Furthermore, cosedimentation experiments demonstrated that tropomyosin bound glutathionylated F-actin with significantly reduced cooperativity. Therefore, glutathionylated actin may be a novel contributor to the diverse set of posttranslational modifications that define the function of the contractile filaments during ischemia-reperfusion injury.

scholarly journals Carbon monoxide protects the kidney through the central circadian clock and CD39

2018 ◽  
Vol 115 (10) ◽  
pp. E2302-E2310 ◽  
Author(s):  
Matheus Correa-Costa ◽  
David Gallo ◽  
Eva Csizmadia ◽  
Edward Gomperts ◽  
Judith-Lisa Lieberum ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Circadian Rhythm ◽  
Organ Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Purinergic Signaling ◽  
Ischemia Reperfusion ◽  
Neutralizing Antibody ◽  
Fold Increase ◽  
Signaling Mechanism ◽  
Tissue Recovery

Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39−/− and Per2−/− mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.

scholarly journals Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury—An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies

2021 ◽  
Vol 22 (4) ◽  
pp. 1864
Author(s):  
Norbert Nemeth ◽  
Katalin Peto ◽  
Zsuzsanna Magyar ◽  
Zoltan Klarik ◽  
Gabor Varga ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tissue Perfusion ◽  
Comprehensive Overview ◽  
Hepatic Ischemia ◽  
Continuous Increase ◽  
Ischemic Conditioning ◽  
Stress Dependent

Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular–pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.

Abstract 204: HAX-1: A Novel Regulator of Energetics and Oxidative Stress in the Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chi K Lam ◽  
Wen Zhao ◽  
Wenfeng Cai ◽  
Guansheng Liu ◽  
Phil Bidwell ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Calcium Handling ◽  
Calcium Kinetics ◽  
Atp Production ◽  
Homologous Protein ◽  
Induced Apoptosis ◽  
Factor C

Sarcoplasmic reticulum (SR) calcium handling is central not only in the control of heart function during excitation-contraction coupling but also in mitochondrial energetics and apoptosis. Recent studies have identified the anti-apoptotic protein, HS-1 associated protein X-1 (HAX-1) as a novel regulator of SR calcium cycling. Although HAX-1 has been shown to localize to mitochondria in various tissues, we found out that it also localizes to SR through its interaction with phospholamban (PLN) in cardiac muscle. Acute or chronic overexpression of HAX-1 in cardiomyocytes promoted PLN inhibition on the calcium ATPase (SERCA) and decreased cardiomyocyte calcium kinetics and contractile parameters. Accordingly, ablation of HAX-1 significantly enhanced SERCA activity and calcium kinetics. Furthermore, the HAX-1/PLN interaction appeared to also regulate cardiomyocyte survival. Indeed, overexpression of HAX-1 and the associated depressed SR Ca-load attenuated endoplasmic reticulum stress induced apoptosis, as evidenced by reduction of both caspase-12 activation and pro-apoptotic transcription factor C/EBP homologous protein induction during ischemia/reperfusion injury. In addition, the depressed SR Ca-cycling by HAX-1 overexpression was associated with reduced mitochondrial Ca-load as reflected by: a) hyper-phosphorylation of pyruvate dehydrogenase (PDH) and decreases in its activity, to diminish ATP production consistent with the attenuated energetic demand in these hearts; and b) reduced levels of reactive oxygen species, indicating protection from oxidative damage and preserved mitochondrial integrity. These findings suggest that HAX-1 is a key regulator of Ca-cycling, apoptosis and energetics in the heart. Thus, decreases in HAX-1 levels, observed during ischemia/reperfusion injury, may contribute to the deteriorated function and progression to heart failure development.

scholarly journals Phytic Acid Protects against 6-Hydroxydopamine-Induced Dopaminergic Neuron Apoptosis in Normal and Iron Excess Conditions in a Cell Culture Model

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Qi Xu ◽  
Anumantha G. Kanthasamy ◽  
Manju B. Reddy
Keyword(s):  
Dna Fragmentation ◽  
Phytic Acid ◽  
Caspase 3 ◽  
Fold Increase ◽  
Iron Chelator ◽  
Culture Model ◽  
A Cell ◽  
Induced Apoptosis ◽  
6 Hydroxydopamine ◽  
Stress Dependent

Iron may play an important role in Parkinson's disease (PD) since it can induce oxidative stress-dependent neurodegeneration. The objective of this study was to determine whether the iron chelator, phytic acid (IP6) can protect against 6-hydroxydopamine- (6-OHDA-) induced apoptosis in immortalized rat mesencephalic dopaminergic cells under normal and iron-excess conditions. Caspase-3 activity was increased about 6-fold after 6-OHDA treatment (compared to control; ) and 30 μmol/L IP6 pretreatment decreased it by 38% (). Similarly, a 63% protection () against 6-OHDA induced DNA fragmentation was observed with IP6 pretreatment. Under iron-excess condition, a 6-fold increase in caspase-3 activity () and a 42% increase in DNA fragmentation () with 6-OHDA treatment were decreased by 41% () and 27% (), respectively, with 30 μmol/L IP6. Together, our data suggest that IP6 protects against 6-OHDA-induced cell apoptosis in both normal and iron-excess conditions, and IP6 may offer neuroprotection in PD.

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