Cardioprotection from ischemia-reperfusion injury due to Ras-GTPase inhibition is attenuated by glibenclamide in the globally ischemic heart

2007 ◽  
Vol 25 (4) ◽  
pp. 455-461 ◽  
Author(s):  
Ibrahim Al-Rashdan ◽  
Halit Canatan ◽  
May Al-Maghrebi ◽  
Mariam H. M. Yousif ◽  
Shah A. Khan ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Ras Gtpase

Abstract 204: Modification of AIFm2 By 4HNE Leads to Retrograde Stress Signaling During Ischemia- Reperfusion Injury in Heart

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sudha Sharma ◽  
Susmita Bhattarai ◽  
Utsab Subedi ◽  
Christina Acosta ◽  
Hosne Ara ◽  
...  
Keyword(s):  
Protein Expression ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adaptor Protein ◽  
Ischemic Heart ◽  
Spectrometric Analysis ◽  
Apoptosis Inducing Factor ◽  
First Time

Myocardial infarction is a leading cause of death worldwide and occurs due to blockage in blood supply to the heart. Re-establishment of blood flow after a brief period of ischemia leads to paradoxical exacerbation of the cardiomyocyte and its death. This phenomenon is known as ischemia-reperfusion injury. Major evidence in the pathogenesis of ischemia-reperfusion injury is due to oxidative stress, which is an imbalance between reactive oxygen species (ROS) and antioxidants. Membrane consisting of polyunsaturated fatty acid is attacked by ROS leading to lipid peroxidation and the generation of one of the toxic aldehydes 4-hydroxynonenal (4-HNE). Evidence suggests that 4-HNE increases during an ischemia-reperfusion injury in the heart. Apoptosis-inducing factor, mitochondrion-associated 2 (AIFM2) is a mitochondrial located oxidoreductase that participates in caspase-independent apoptosis. In this study, we sought to identify the role of 4-HNE in regulating AIFm2 translocation and cardiomyocyte death during an ischemia-reperfusion injury in the heart. Following ischemia both RNA and protein expression of AIFm2 significantly increased in the ischemic heart compared to sham. Also, 4-HNE adducted AIFm2 translocated from mitochondria to the nucleus shown by western blot analysis in ischemic heart. The mass spectrometric analysis was done to see the modification site on AIFm2 by 4-HNE and revealed that His 174 and Cys 187 are two sites on AIFm2 where 4-HNE adduction occurred. To identify the modification site responsible for AIFm2 translocation we performed site-direct mutagenesis in H9C2 cardiomyocyte, where Histidine 174 was replaced by arginine and Cys 187 was replaced by threonine. When the ischemia-reperfusion injury was induced, only Histidine 174 mutant failed to translocate to the nucleus indicating His 174 modification by 4-HNE was responsible for AIFm2 translocation. To further support the transport mechanism, protein expression of Importin; an adaptor protein responsible for the transfer of proteins to the nucleus was increased in the ischemic heart compared to sham. Collectively, those results for the first time identify the unique role of 4-HNE modification on AIFm2 protein during an ischemia-reperfusion injury in the heart.

scholarly journals Inorganic arsenic exposure induces sex-disparate effects and exacerbates ischemia-reperfusion injury in the female heart

2019 ◽  
Vol 316 (5) ◽  
pp. H1053-H1064 ◽  
Author(s):  
Ryne Veenema ◽  
Kevin M. Casin ◽  
Prithvi Sinha ◽  
Raihan Kabir ◽  
Nathan Mackowski ◽  
...  
Keyword(s):  
Drinking Water ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inorganic Arsenic ◽  
Ischemic Heart ◽  
Male And Female ◽  
Female Mice ◽  
17Β Estradiol ◽  
Heart Injury

Arsenic is a common contaminant in drinking water throughout the world, and recent studies support a link between inorganic arsenic (iAS) exposure and ischemic heart disease in men and women. Female hearts exhibit an estrogen-dependent reduction in susceptibility to myocardial ischemic injury compared with males, and as such, female hearts may be more susceptible to the endocrine-disrupting effects of iAS exposure. However, iAS exposure and susceptibility to ischemic heart injury have not been examined in mechanistic studies. Male and female mice (8 wk) were exposed to environmentally relevant concentrations of sodium arsenite (0, 10, 100, and 1,000 parts/billion) via drinking water for 4 wk. Pre- and postexposure echocardiography was performed, and postexposure plasma was collected for 17β-estradiol measurement. Hearts were excised and subjected to ischemia-reperfusion (I/R) injury via Langendorff perfusion. Exposure to 1,000 parts/billion iAS led to sex-disparate effects, such that I/R injury was exacerbated in female hearts but unexpectedly attenuated in males. Assessment of echocardiographic parameters revealed statistically significant structural remodeling in iAS-treated female hearts with no change in function; males showed no change. Plasma 17β-estradiol levels were not significantly altered by iAS in male or female mice versus nontreated controls. Although total eNOS protein levels did not change in whole heart homogenates from iAS-treated male or female mice, eNOS phosphorylation (Ser1177) was significantly elevated in iAS-treated male hearts. These results suggest that iAS exposure can induce sex-disparate effects and modulate susceptibility to ischemic heart injury by targeting distinct sex-dependent pathways. NEW & NOTEWORTHY This is the first mechanistic study examining iAS exposure on myocardial ischemia-reperfusion injury in male and female mice. Following iAS exposure, ischemia-reperfusion injury was exacerbated in female hearts but attenuated in males. iAS treatment induced statistically significant cardiac remodeling in females, with no change in males. iAS treatment also enhanced phosphorylated eNOS levels at Ser1177, but only in male hearts. These results suggest that iAS alters susceptibility to myocardial I/R injury through distinct sex-dependent pathways.

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

2011 ◽  
Vol 301 (5) ◽  
pp. H1723-H1741 ◽  
Author(s):  
Shoji Sanada ◽  
Issei Komuro ◽  
Masafumi Kitakaze
Keyword(s):  
Reperfusion Injury ◽  
Clinical Evidence ◽  
Clinical Medicine ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Developed Countries ◽  
Adverse Outcomes ◽  
Ischemic Heart ◽  
Pathophysiological Mechanism

Heart diseases due to myocardial ischemia, such as myocardial infarction or ischemic heart failure, are major causes of death in developed countries, and their number is unfortunately still growing. Preliminary exploration into the pathophysiology of ischemia-reperfusion injury, together with the accumulation of clinical evidence, led to the discovery of ischemic preconditioning, which has been the main hypothesis for over three decades for how ischemia-reperfusion injury can be attenuated. The subcellular pathophysiological mechanism of ischemia-reperfusion injury and preconditioning-induced cardioprotection is not well understood, but extensive research into components, including autacoids, ion channels, receptors, subcellular signaling cascades, and mitochondrial modulators, as well as strategies for modulating these components, has made evolutional progress. Owing to the accumulation of both basic and clinical evidence, the idea of ischemic postconditioning with a cardioprotective potential has been discovered and established, making it possible to apply this knowledge in the clinical setting after ischemia-reperfusion insult. Another a great outcome has been the launch of translational studies that apply basic findings for manipulating ischemia-reperfusion injury into practical clinical treatments against ischemic heart diseases. In this review, we discuss the current findings regarding the fundamental pathophysiological mechanisms of ischemia-reperfusion injury, the associated protective mechanisms of ischemic pre- and postconditioning, and the potential seeds for molecular, pharmacological, or mechanical treatments against ischemia-reperfusion injury, as well as subsequent adverse outcomes by modulation of subcellular signaling mechanisms (especially mitochondrial function). We also review emerging translational clinical trials and the subsistent clinical comorbidities that need to be overcome to make these trials applicable in clinical medicine.

scholarly journals The mechanism of miR-525-5p derived from hypoxia and reoxygenation in H9c2 Cardiomyocytes

2022 ◽  
Vol 67 (4) ◽  
pp. 18-23
Author(s):  
Shanshan Wang ◽  
Xin Mei ◽  
Song Ronggang ◽  
Meng Hongyan ◽  
Wei Xinfen
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Reperfusion Injury ◽  
Mrna Expression ◽  
Gene Mutation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
H9c2 Cells ◽  
H9c2 Cardiomyocytes

Ischemia-reperfusion injury (IRI) is associated with ischemic heart disease (IHD) which leads to patients a poor progression. According to Pubmed Datasets, we analyzed different gene and mRNA expressions in IHD patients with IRI. The relevant mRNA expression detected in H9C2 cells undergo hypoxia and reoxygenation, we selected and structured miR-525-5p gene mutation H9C2 cells, the results performed miR-525-5p mutated restored H9C2 metabolism of mitochondria which detected by relevant genes and proteins. At the same time, miR-525-5p silence resisted hypoxia and reoxygenation induced H9C2 cells apoptosis. All the results indicated miR-525-5p maybe protect H9C2 cells without hypoxia and reoxygenation induced injury through regulating the mitochondria metabolism.

scholarly journals From Brain to Heart: Possible Role of Amyloid-β in Ischemic Heart Disease and Ischemia-Reperfusion Injury

2020 ◽  
Vol 21 (24) ◽  
pp. 9655
Author(s):  
Giulia Gagno ◽  
Federico Ferro ◽  
Alessandra Lucia Fluca ◽  
Milijana Janjusevic ◽  
Maddalena Rossi ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Reperfusion Injury ◽  
Coronary Atherosclerosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Amyloid Β ◽  
Ischemic Heart ◽  
Amyloid Angiopathy

Ischemic heart disease (IHD) is among the leading causes of death in developed countries. Its pathological origin is traced back to coronary atherosclerosis, a lipid-driven immuno-inflammatory disease of the arteries that leads to multifocal plaque development. The primary clinical manifestation of IHD is acute myocardial infarction (AMI),) whose prognosis is ameliorated with optimal timing of revascularization. Paradoxically, myocardium re-perfusion can be detrimental because of ischemia-reperfusion injury (IRI), an oxidative-driven process that damages other organs. Amyloid-β (Aβ) plays a physiological role in the central nervous system (CNS). Alterations in its synthesis, concentration and clearance have been connected to several pathologies, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ has been suggested to play a role in the pathogenesis of IHD and cerebral IRI. The purpose of this review is to summarize what is known about the pathological role of Aβ in the CNS; starting from this evidence, we will illustrate the role played by Aβ in the development of coronary atherosclerosis and its possible implications in the pathophysiology of IHD and myocardial IRI. Better elucidation of Aβ’s contribution to the molecular pathways underlying IHD and IRI could be of great help in developing new therapeutic strategies.

Abstract 144: Cardiac Expression of Mitochondrial Acetyltransferase Gcn5l1 Contributes to Ischemia-Reperfusion Injury and Alters Mitochondrial Energetics After Injury

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Janet R Manning ◽  
Dharendra Thapa ◽  
Manling Zhang ◽  
Michael W Stoner ◽  
Iain Scott
Keyword(s):  
Heart Failure ◽  
Reperfusion Injury ◽  
Protein Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Ischemic Heart ◽  
Mitochondrial Proteins ◽  
Ros Production ◽  
Triphenyltetrazolium Chloride

Introduction: The increasing global burden of ischemic heart disease demands a closer examination of the mechanisms by which myocardial reperfusion produces injury to initiate long-term heart failure. Reactive oxygen species (ROS) generated after ischemia reperfusion (IR), in conjunction with the dysfunction of mitochondrial metabolic enzymes, have been identified as a primary mediator of cardiac reperfusion injury. The acetylation of mitochondrial proteins, regulated by opposing actions of NAD + -dependent sirtuin deacetylases and the recently identified mitochondrial acetyltransferase GCN5L1, has emerged as a key point of intersection between nutrient status and mitochondrial protein function in cardiomyoctyes. This makes the association between acetylation and ROS production an important topic of investigation. Intriguingly, global protein acetylation was recently reported to be upregulated in the hearts of human patients with ischemic heart failure. Despite this, it remains unknown whether GCN5L1 acetyltransferase activity plays a role in the regulation of metabolic proteins during IR injury. Hypothesis: Cardiac deletion of the acetyltransferase GCN5L1 reduces the acetylation of mitochondrial proteins during IR, reducing aberrant activity and preventing ROS production. Methods: Isolated work-performing hearts from cardiac-specific inducible GCN5L1 knockout mice were subjected to global ischemia and reperfusion. Contractility (+/- dP/dT) of the left ventricle was measured throughout as an index of post IR functional recovery. Tissue damage was assessed by measuring the release of lactate dehydrogenase and post-reperfusion staining of viable tissue with triphenyltetrazolium chloride. Acetylation levels of mitochondrial proteins were measured during IR using immunoblotting of homogenized hearts, which were also used to evaluate ROS production. Results and Conclusions: Mitochondrial acetylation was decreased in GCN5L1 hearts compared to WT, coinciding with improved post-IR recovery. We therefore conclude that acetylation of mitochondrial proteins by the acetyltransferase GCN5L1 is an important regulatory mechanism of IR-induced, ROS-mediated damage.

scholarly journals Na/K-ATPase Signaling and Cardiac Pre/Postconditioning with Cardiotonic Steroids

2018 ◽  
Vol 19 (8) ◽  
pp. 2336 ◽  
Author(s):  
Pauline Marck ◽  
Sandrine Pierre
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Clinical Research ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Low Concentrations ◽  
Cardioprotective Action

The first reports of cardiac Na/K-ATPase signaling, published 20 years ago, have opened several major fields of investigations into the cardioprotective action of low/subinotropic concentrations of cardiotonic steroids (CTS). This review focuses on the protective cardiac Na/K-ATPase-mediated signaling triggered by low concentrations of ouabain and other CTS, in the context of the enduring debate over the use of CTS in the ischemic heart. Indeed, as basic and clinical research continues to support effectiveness and feasibility of conditioning interventions against ischemia/reperfusion injury in acute myocardial infarction (AMI), the mechanistic information available to date suggests that unique features of CTS-based conditioning could be highly suitable, alone /or as a combinatory approach.

scholarly journals Effects of endogenous cardioprotective mechanisms on ischemia-reperfusion injury

2017 ◽  
Vol 71 (0) ◽  
pp. 20-31 ◽  
Author(s):  
Marcin Kunecki ◽  
Wojciech Płazak ◽  
Piotr Podolec ◽  
Krzysztof S. Gołba
Keyword(s):  
Reperfusion Injury ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Heart Muscle ◽  
Human Heart ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Receptor Activation ◽  
Membrane Receptors ◽  
Ischemic Heart

Ischemic heart disease have been remarked as a leading cause of morbidity and mortality in adults. Early restoration of cardiac perfusion is necessary to restore perfusion of ischemic heart muscle. Effective revascularization reduce mortality by limiting myocardial necrosis at the acute phase of the cardiac infarction. However, reperfusion may induce a cascade of pathophysiological reactions causing the increase of the infarct area of the myocardium This phenomenon known as ischemia-reperfusion injury is responsible for up to 50% of the final infarct size. Sequences of brief episodes of nonlethal ischemia and reperfusion applied before (preconditioning — IPC) or after (postconditioning — POC) the coronary occlusion are well documented to reduce the ischemiareperfusion injury. These phenomena improve cardiac function by mobilizing the molecular and cellular mechanisms limiting reperfusion injury. The mechanisms underlying IPC or POC are still not clarified, but strong experimental evidence suggests that opioids may be the part of the endogenous cardioprotective response to I/R injury. Stimulation of opioid receptors activates related to POC mechanisms affecting protection to the ischemic myocardium, while the use of non-selective opioid receptor antagonist - naloxone reduces this effect. There is no consensus that the subtype of opioid receptor is responsible for the protection of the human heart muscle.Morphine may reduce cardiac preload by peripheral vasodilatation. Numerous studies show a direct cardioprotective effect of the opioid pathway in ischemic conditions. Opioids act via membrane receptors: μ, δ, κ. The predominant subtype in the human cardiac cells are μ- and δ – opioid receptors. It has been hypothetized that opioid receptor activation exerts cardioprotection in human heart muscle pathway what may give insight into the explanation of the protective mechanisms in the acute myocardial infarction.

scholarly journals Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Lei Pang ◽  
Yin Cai ◽  
Eva Hoi Ching Tang ◽  
Michael G. Irwin ◽  
Haichun Ma ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Prostaglandin E ◽  
Ischemic Heart Diseases ◽  
Ep4 Receptor ◽  
Arachidonic Acids

Prostaglandin E2(PGE2) is an endogenous lipid mediator, produced from the metabolism of arachidonic acids, upon the sequential actions of phospholipase A2, cyclooxygenases, and prostaglandin E synthases. The various biological functions governed by PGE2are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE2-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE2-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia/reperfusion injury. A better understanding of PGE2-EP4 signaling should promote the development of more effective therapeutic approaches to treat the ischemic heart diseases without triggering unwanted side effects.

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