Molecular and Cellular Mechanisms of Ischemia-Reperfusion Injury and Protective Strategies

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cells of the Cardiovascular System".

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Editors


E-Mail Website
Collection Editor
1. Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
2. CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Interests: ischemia-reperfusion injury; myocardial infarction; gap junctions; connexin 43; mitochondrial; succinate dehydrogenase; heart failure

E-Mail Website
Collection Editor
1. Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
2. CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Interests: mitochondria; calcium; AGEs; aging; ischemia/reperfusion injury; heart failure

E-Mail Website
Collection Editor
1. Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
2. CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
Interests: myocardial ischemia/reperfusion injury; heart failure; calpains; fibrosis; hypertrophy; nitric oxide; guanylate cyclase

Topical Collection Information

Dear Colleagues,

Ischemic disorders are a leading cause of death and disability worldwide, and affect multiple organs, including the heart, brain, kidney and the gut, among others. Several conditions, such as acute coronary syndrome, sepsis, thromboembolism, organ transplantation or limb injury, may produce tissue hypoperfusion and ischemia. The treatment of choice for patients suffering from tissue ischemia is the immediate restoration of blood flow. However, and despite the correct and rapid application of blood flow restoration techniques, reperfusion protocols do not prevent the occurrence of extensive cell death and tissue necrosis in a significant fraction of patients. This is, in part, due to the fact that blood flow restoration can itself cause a paradoxical exacerbation of injury, a phenomenon termed reperfusion injury. Importantly, reperfusion injury can be prevented by treatments applied at the onset of reflow, which presents a promising therapeutic opportunity. However, the protective effect of most of these treatments has not been confirmed in clinical trials. Therefore, it is essential to increase our knowledge on the pathophysiology of ischemia-reperfusion injury, to be able to propose new therapeutic approaches specifically addressed to mitigate it.

This Topical Collection aims to summarize the current knowledge on the molecular and cellular mechanisms of ischemia-reperfusion injury, to explore tissue specific differences, and to identify potential therapeutic strategies capable of reducing cell death and dysfunction that could, eventually, be applied to patients.

We look forward to your contributions.

Dr. Antonio Rodríguez-Sinovas
Dr. Marisol Ruiz-Meana
Dr. Javier Inserte
Collection Editors

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Keywords

  • reperfusion injury
  • ischemia
  • infarct
  • stroke
  • conditioning
  • cardioprotection
  • mitochondria
  • heart
  • kidney
  • brain
  • gut
  • limb

Published Papers (12 papers)

2023

Jump to: 2021, 2020

18 pages, 1561 KiB  
Review
NLRP3-Induced NETosis: A Potential Therapeutic Target for Ischemic Thrombotic Diseases?
by Rahul Kumar, Gokul Patil and Sanjana Dayal
Cells 2023, 12(23), 2709; https://doi.org/10.3390/cells12232709 - 26 Nov 2023
Viewed by 1379
Abstract
Ischemic thrombotic disease, characterized by the formation of obstructive blood clots within arteries or veins, is a condition associated with life-threatening events, such as stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism. The conventional therapeutic strategy relies on treatments with anticoagulants that [...] Read more.
Ischemic thrombotic disease, characterized by the formation of obstructive blood clots within arteries or veins, is a condition associated with life-threatening events, such as stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism. The conventional therapeutic strategy relies on treatments with anticoagulants that unfortunately pose an inherent risk of bleeding complications. These anticoagulants primarily target clotting factors, often overlooking upstream events, including the release of neutrophil extracellular traps (NETs). Neutrophils are integral components of the innate immune system, traditionally known for their role in combating pathogens through NET formation. Emerging evidence has now revealed that NETs contribute to a prothrombotic milieu by promoting platelet activation, increasing thrombin generation, and providing a scaffold for clot formation. Additionally, NET components enhance clot stability and resistance to fibrinolysis. Clinical and preclinical studies have underscored the mechanistic involvement of NETs in the pathogenesis of thrombotic complications, since the clots obtained from patients and experimental models consistently exhibit the presence of NETs. Given these insights, the inhibition of NETs or NET formation is emerging as a promising therapeutic approach for ischemic thrombotic diseases. Recent investigations also implicate a role for the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome as a mediator of NETosis and thrombosis, suggesting that NLRP3 inhibition may also hold potential for mitigating thrombotic events. Therefore, future preclinical and clinical studies aimed at identifying and validating NLRP3 inhibition as a novel therapeutic intervention for thrombotic disorders are imperative. Full article
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14 pages, 2232 KiB  
Article
Complement C3 Reduces Apoptosis via Interaction with the Intrinsic Apoptotic Pathway
by Zhou Fang, Haekyung Lee, Junying Liu, Karen A. Wong, Lewis M. Brown, Xiang Li, Alus M. Xiaoli, Fajun Yang and Ming Zhang
Cells 2023, 12(18), 2282; https://doi.org/10.3390/cells12182282 - 15 Sep 2023
Viewed by 923
Abstract
Myocardial ischemia/reperfusion (I/R) elicits an acute inflammatory response involving complement factors. Recently, we reported that myocardial necrosis was decreased in complement C3−/− mice after heart I/R. The current study used the same heart model to test the effect of C3 on myocardial [...] Read more.
Myocardial ischemia/reperfusion (I/R) elicits an acute inflammatory response involving complement factors. Recently, we reported that myocardial necrosis was decreased in complement C3−/− mice after heart I/R. The current study used the same heart model to test the effect of C3 on myocardial apoptosis and investigated if C3 regulation of apoptosis occurred in human cardiomyocytes. Comparative proteomics analyses found that cytochrome c was present in the myocardial C3 complex of WT mice following I/R. Incubation of exogenous human C3 reduced apoptosis in a cell culture system of human cardiomyocytes that did not inherently express C3. In addition, human C3 inhibited the intrinsic apoptosis pathway in a cell-free apoptosis system. Finally, human pro-C3 was found to bind with an apoptotic factor, pro-caspase 3, in a cell-free system. Thus, we present firsthand evidence showing that C3 readily reduces myocardial apoptosis via interaction with the intrinsic apoptotic pathway. Full article
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2021

Jump to: 2023, 2020

16 pages, 758 KiB  
Review
Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation
by Manuela Zinni, Julien Pansiot, Pierre-Louis Léger, Marina El Kamouh and Olivier Baud
Cells 2021, 10(10), 2766; https://doi.org/10.3390/cells10102766 - 15 Oct 2021
Cited by 9 | Viewed by 3367
Abstract
Cerebral stroke, traumatic brain injury, and hypoxic ischemic encephalopathy are among the most frequently occurring brain injuries. A complex pathogenesis, characterized by a synergistic interaction between alterations of the cerebrovascular system, cell death, and inflammation, is at the basis of the brain damage [...] Read more.
Cerebral stroke, traumatic brain injury, and hypoxic ischemic encephalopathy are among the most frequently occurring brain injuries. A complex pathogenesis, characterized by a synergistic interaction between alterations of the cerebrovascular system, cell death, and inflammation, is at the basis of the brain damage that leads to behavioral and neurodevelopmental disabilities in affected subjects. Sildenafil is a selective inhibitor of the enzyme phosphodiesterase 5 (PDE5) that is able to cross the blood–brain barrier. Preclinical data suggest that sildenafil may be a good candidate for the prevention or repair of brain injury in both adults and neonates. The aim of this review is to summarize the evidence supporting the neuroprotective action of sildenafil and discuss the possible benefits of the association of sildenafil with current therapeutic strategies. Full article
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20 pages, 1013 KiB  
Review
Brain Immune Interactions—Novel Emerging Options to Treat Acute Ischemic Brain Injury
by Sajjad Muhammad, Shafqat Rasul Chaudhry, Ulf Dietrich Kahlert, Mika Niemelä and Daniel Hänggi
Cells 2021, 10(9), 2429; https://doi.org/10.3390/cells10092429 - 15 Sep 2021
Cited by 14 | Viewed by 3498
Abstract
Ischemic stroke is still among the leading causes of mortality and morbidity worldwide. Despite intensive advancements in medical sciences, the clinical options to treat ischemic stroke are limited to thrombectomy and thrombolysis using tissue plasminogen activator within a narrow time window after stroke. [...] Read more.
Ischemic stroke is still among the leading causes of mortality and morbidity worldwide. Despite intensive advancements in medical sciences, the clinical options to treat ischemic stroke are limited to thrombectomy and thrombolysis using tissue plasminogen activator within a narrow time window after stroke. Current state of the art knowledge reveals the critical role of local and systemic inflammation after stroke that can be triggered by interactions taking place at the brain and immune system interface. Here, we discuss different cellular and molecular mechanisms through which brain–immune interactions can take place. Moreover, we discuss the evidence how the brain influence immune system through the release of brain derived antigens, damage-associated molecular patterns (DAMPs), cytokines, chemokines, upregulated adhesion molecules, through infiltration, activation and polarization of immune cells in the CNS. Furthermore, the emerging concept of stemness-induced cellular immunity in the context of neurodevelopment and brain disease, focusing on ischemic implications, is discussed. Finally, we discuss current evidence on brain–immune system interaction through the autonomic nervous system after ischemic stroke. All of these mechanisms represent potential pharmacological targets and promising future research directions for clinically relevant discoveries. Full article
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13 pages, 2651 KiB  
Communication
Transcriptomic Hallmarks of Ischemia-Reperfusion Injury
by Mandana Movahed, Sydney Brockie, James Hong and Michael G. Fehlings
Cells 2021, 10(7), 1838; https://doi.org/10.3390/cells10071838 - 20 Jul 2021
Cited by 13 | Viewed by 3838
Abstract
Ischemia reperfusion injury (IRI) is associated with a broad array of life-threatening medical conditions including myocardial infarct, cerebral stroke, and organ transplant. Although the pathobiology and clinical manifestations of IRI are well reviewed by previous publications, IRI-related transcriptomic alterations are less studied. This [...] Read more.
Ischemia reperfusion injury (IRI) is associated with a broad array of life-threatening medical conditions including myocardial infarct, cerebral stroke, and organ transplant. Although the pathobiology and clinical manifestations of IRI are well reviewed by previous publications, IRI-related transcriptomic alterations are less studied. This study aimed to reveal a transcriptomic hallmark for IRI by using the RNA-sequencing data provided by several studies on non-human preclinical experimental models. In this regard, we focused on the transcriptional responses of IRI in an acute time-point up to 48 h. We compiled a list of highly reported genes in the current literature that are affected in the context of IRI. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and found many of the up-regulated genes to be involved in cell survival, cell surface signaling, response to oxidative stress, and inflammatory response, while down-regulated genes were predominantly involved in ion transport. Furthermore, by GO analysis, we found that multiple inflammatory and stress response processes were affected after IRI. Tumor necrosis factor alpha (TNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways were also highlighted in the Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In the last section, we discuss the treatment approaches and their efficacy for IRI by comparing RNA sequencing data from therapeutic interventions with the results of our cross-comparison of differentially expressed genes and pathways across IRI. Full article
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11 pages, 9746 KiB  
Review
Brain Protection after Anoxic Brain Injury: Is Lactate Supplementation Helpful?
by Filippo Annoni, Lorenzo Peluso, Elisa Gouvêa Bogossian, Jacques Creteur, Elisa R. Zanier and Fabio Silvio Taccone
Cells 2021, 10(7), 1714; https://doi.org/10.3390/cells10071714 - 06 Jul 2021
Cited by 16 | Viewed by 3712
Abstract
While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss [...] Read more.
While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss of perfusion to the brain, determining a whole brain ischemic-anoxic injury. Differently from other threatening situations of reduced cerebral perfusion, i.e., caused by increased intracranial pressure or circulatory shock, resuscitated patients after a cardiac arrest experience a sudden restoration of cerebral blood flow and are exposed to a massive reperfusion injury, which could significantly alter cellular metabolism. Current evidence suggests that cell populations in the central nervous system might use alternative metabolic pathways to glucose and that neurons may rely on a lactate-centered metabolism. Indeed, lactate does not require adenosine triphosphate (ATP) to be oxidated and it could therefore serve as an alternative substrate in condition of depleted energy reserves, i.e., reperfusion injury, even in presence of adequate tissue oxygen delivery. Lactate enriched solutions were studied in recent years in healthy subjects, acute heart failure, and severe traumatic brain injured patients, showing possible benefits that extend beyond the role as alternative energetic substrates. In this manuscript, we addressed some key aspects of the cellular metabolic derangements occurring after cerebral ischemia-reperfusion injury and examined the possible rationale for the administration of lactate enriched solutions in resuscitated patients after cardiac arrest. Full article
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14 pages, 3127 KiB  
Article
Myostatin Deficiency Protects C2C12 Cells from Oxidative Stress by Inhibiting Intrinsic Activation of Apoptosis
by Marius Drysch, Sonja Verena Schmidt, Mustafa Becerikli, Felix Reinkemeier, Stephanie Dittfeld, Johannes Maximilian Wagner, Mehran Dadras, Alexander Sogorski, Maxi von Glinski, Marcus Lehnhardt, Björn Behr and Christoph Wallner
Cells 2021, 10(7), 1680; https://doi.org/10.3390/cells10071680 - 03 Jul 2021
Cited by 10 | Viewed by 3043
Abstract
Ischemia reperfusion (IR) injury remains an important topic in clinical medicine. While a multitude of prophylactic and therapeutic strategies have been proposed, recent studies have illuminated protective effects of myostatin inhibition. This study aims to elaborate on the intracellular pathways involved in myostatin [...] Read more.
Ischemia reperfusion (IR) injury remains an important topic in clinical medicine. While a multitude of prophylactic and therapeutic strategies have been proposed, recent studies have illuminated protective effects of myostatin inhibition. This study aims to elaborate on the intracellular pathways involved in myostatin signaling and to explore key proteins that convey protective effects in IR injury. We used CRISPR/Cas9 gene editing to introduce a myostatin (Mstn) deletion into a C2C12 cell line. In subsequent experiments, we evaluated overall cell death, activation of apoptotic pathways, ROS generation, lipid peroxidation, intracellular signaling via mitogen-activated protein kinases (MAPKs), cell migration, and cell proliferation under hypoxic conditions followed by reoxygenation to simulate an IR situation in vitro (hypoxia reoxygenation). It was found that mitogen-activated protein kinase kinase 3/6, also known as MAPK/ERK Kinase 3/6 (MEK3/6), and subsequent p38 MAPK activation were blunted in C2C12-Mstn−/− cells in response to hypoxia reoxygenation (HR). Similarly, c-Jun N-terminal kinase (JNK) activation was negated. We also found the intrinsic activation of apoptosis to be more important in comparison with the extrinsic activation. Additionally, intercepting myostatin signaling mitigated apoptosis activation. Ultimately, this research validated protective effects of myostatin inhibition in HR and identified potential mediators worth further investigation. Intercepting myostatin signaling did not inhibit ROS generation overall but mitigated cellular injury. In particular, intrinsic activation of apoptosis origination from mitochondria was alleviated. This was presumably mediated by decreased activation of p38 caused by the diminished kinase activity increase of MEK3/6. Overall, this work provides important insights into HR signaling in C2C12-Mstn−/− cells and could serve as basis for further research. Full article
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26 pages, 1267 KiB  
Review
Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury
by Ivó H. Hernández, Mario Villa-González, Gerardo Martín, Manuel Soto and María José Pérez-Álvarez
Cells 2021, 10(7), 1639; https://doi.org/10.3390/cells10071639 - 30 Jun 2021
Cited by 49 | Viewed by 8926
Abstract
Ischemic stroke is the second cause of mortality and the first cause of long-term disability constituting a serious socioeconomic burden worldwide. Approved treatments include thrombectomy and rtPA intravenous administration, which, despite their efficacy in some cases, are not suitable for a great proportion [...] Read more.
Ischemic stroke is the second cause of mortality and the first cause of long-term disability constituting a serious socioeconomic burden worldwide. Approved treatments include thrombectomy and rtPA intravenous administration, which, despite their efficacy in some cases, are not suitable for a great proportion of patients. Glial cell-related therapies are progressively overcoming inefficient neuron-centered approaches in the preclinical phase. Exploiting the ability of microglia to naturally switch between detrimental and protective phenotypes represents a promising therapeutic treatment, in a similar way to what happens with astrocytes. However, the duality present in many of the roles of these cells upon ischemia poses a notorious difficulty in disentangling the precise pathways to target. Still, promoting M2/A2 microglia/astrocyte protective phenotypes and inhibiting M1/A1 neurotoxic profiles is globally rendering promising results in different in vivo models of stroke. On the other hand, described oligodendrogenesis after brain ischemia seems to be strictly beneficial, although these cells are the less studied players in the stroke paradigm and negative effects could be described for oligodendrocytes in the next years. Here, we review recent advances in understanding the precise role of mentioned glial cell types in the main pathological events of ischemic stroke, including inflammation, blood brain barrier integrity, excitotoxicity, reactive oxygen species management, metabolic support, and neurogenesis, among others, with a special attention to tested therapeutic approaches. Full article
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10 pages, 1218 KiB  
Article
Succinate Injection Rescues Vasculature and Improves Functional Recovery Following Acute Peripheral Ischemia in Rodents: A Multimodal Imaging Study
by Anaïs Moyon, Philippe Garrigue, Laure Balasse, Samantha Fernandez, Pauline Brige, Ahlem Bouhlel, Guillaume Hache, Françoise Dignat-George, David Taïeb and Benjamin Guillet
Cells 2021, 10(4), 795; https://doi.org/10.3390/cells10040795 - 02 Apr 2021
Cited by 4 | Viewed by 2181
Abstract
Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study [...] Read more.
Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study was conducted with ischemic mice treated with succinate or PBS and evaluated by imaging. Acute ischemia was followed by an increased in GPR91 expression in the ischemic muscle. As assessed with LASER-Doppler, succinate treatment resulted in an earlier and more intense reperfusion of the ischemic hindlimb compared to the control group (* p = 0.0189). A microPET study using a radiolabeled integrin ligand ([68Ga]Ga-RGD2) showed an earlier angiogenic activation in the succinate arm compared to control mice (* p = 0.020) with a prolonged effect. Additionally, clinical recovery following ischemia was better in the succinate group. In conclusion, succinate injection promotes earlier angiogenesis after ischemia, resulting in a more effective revascularization and subsequently a better functional recovery. Full article
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35 pages, 1820 KiB  
Review
Cellular and Molecular Mechanisms of R/S-Roscovitine and CDKs Related Inhibition under Both Focal and Global Cerebral Ischemia: A Focus on Neurovascular Unit and Immune Cells
by Lucas Le Roy, Anne Letondor, Cloé Le Roux, Ahmed Amara and Serge Timsit
Cells 2021, 10(1), 104; https://doi.org/10.3390/cells10010104 - 08 Jan 2021
Cited by 7 | Viewed by 2900
Abstract
Ischemic stroke is the second leading cause of death worldwide. Following ischemic stroke, Neurovascular Unit (NVU) inflammation and peripheral leucocytes infiltration are major contributors to the extension of brain lesions. For a long time restricted to neurons, the 10 past years have shown [...] Read more.
Ischemic stroke is the second leading cause of death worldwide. Following ischemic stroke, Neurovascular Unit (NVU) inflammation and peripheral leucocytes infiltration are major contributors to the extension of brain lesions. For a long time restricted to neurons, the 10 past years have shown the emergence of an increasing number of studies focusing on the role of Cyclin-Dependent Kinases (CDKs) on the other cells of NVU, as well as on the leucocytes. The most widely used CDKs inhibitor, (R)-roscovitine, and its (S) isomer both decreased brain lesions in models of global and focal cerebral ischemia. We previously showed that (S)-roscovitine acted, at least, by modulating NVU response to ischemia. Interestingly, roscovitine was shown to decrease leucocytes-mediated inflammation in several inflammatory models. Specific inhibition of roscovitine majors target CDK 1, 2, 5, 7, and 9 showed that these CDKs played key roles in inflammatory processes of NVU cells and leucocytes after brain lesions, including ischemic stroke. The data summarized here support the investigation of roscovitine as a potential therapeutic agent for the treatment of ischemic stroke, and provide an overview of CDK 1, 2, 5, 7, and 9 functions in brain cells and leucocytes during cerebral ischemia. Full article
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2020

Jump to: 2023, 2021

25 pages, 2553 KiB  
Review
The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction
by Alessandro Bellis, Ciro Mauro, Emanuele Barbato, Giuseppe Di Gioia, Daniela Sorriento, Bruno Trimarco and Carmine Morisco
Cells 2020, 9(9), 2134; https://doi.org/10.3390/cells9092134 - 21 Sep 2020
Cited by 12 | Viewed by 3698
Abstract
During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain [...] Read more.
During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a “multi-targeted cardioprotective therapy”, defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention. Full article
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13 pages, 2913 KiB  
Article
HPLC-MS/MS Shows That the Cellular Uptake of All-Trans-Retinoic Acid under Hypoxia Is Downregulated by the Novel Active Agent 5-Methoxyleoligin
by Armin Sebastian Guntner, Christian Doppler, Christian Wechselberger, David Bernhard and Wolfgang Buchberger
Cells 2020, 9(9), 2048; https://doi.org/10.3390/cells9092048 - 08 Sep 2020
Cited by 4 | Viewed by 2799
Abstract
All-trans-retinoic acid (atRA) is the essential derivative of vitamin A and is of interest due to its various biological key functions. As shown in the recent literature, atRA also plays a role in the failing heart during [...] Read more.
All-trans-retinoic acid (atRA) is the essential derivative of vitamin A and is of interest due to its various biological key functions. As shown in the recent literature, atRA also plays a role in the failing heart during myocardial infarction, the leading cause of death globally. To date insufficient mechanistic information has been available on related hypoxia-induced cell damage and reperfusion injuries. However, it has been demonstrated that a reduction in cellular atRA uptake abrogates hypoxia-mediated cell and tissue damage, which may offer a new route for intervention. Consequently, in this study, the effect of the novel cardio-protective compound 5-methoxyleoligin (5ML) on cellular atRA uptake was tested in human umbilical-vein endothelial cells (HUVECs). For this purpose, a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to assess intra-cellular levels of the active substance and corresponding levels of vitamin A and its derivatives, including potential cis/trans isomers. This work also focused on light-induced isomerization and the stability of biological sample material to ensure sample integrity and avoid biased conclusions. This study provides evidence of the inhibitory effect of 5ML on cellular atRA uptake, a promising step toward a novel therapy for myocardial infarction. Full article
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