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Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational...
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Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 17575

Special Issue Editor

Prof. Dr. Macarena Hernández-Jiménez

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, Faculty of Medicine, Complutense University, Madrid, Spain
Interests: stroke; cytoprotection; inflammation; pharmacology; clinical trials

Special Issue Information

Dear Colleagues,

Despite the implementation of therapies for recanalization, stroke remains the second leading cause of death and the first cause of disability in adults worldwide. Several cerebroprotective drugs are currently in clinical trials but, to date, none of them have demonstrate efficacy in large clinical trials. Therefore, the identification of new targets and the development of novel therapeutic approaches is still necessary to improve the patients’ outcomes and quality of life after suffering a stroke. The aim of this Special Issue is to present new therapeutic approaches by taking into account good research practices that guarantee animal wellbeing and provide translational results to support further clinical trials in the stroke field.

Dr. Macarena Hernández-Jiménez
Guest Editor

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Keywords

  • stroke
  • cytoprotection
  • recanalization
  • pharmacology

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Published Papers (9 papers)

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Research

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11 pages, 1784 KiB  
Article
The Effects of Beta-Blockers on Leukocytes and the Leukocyte Subpopulation in Heart Failure Patients
by Anca Daniela Farcaş, Mirela Anca Stoia, Diana Larisa Mocan-Hognogi, Cerasela Mihaela Goidescu, Alexandra Florina Cocoi and Florin Petru Anton
Biomedicines 2024, 12(12), 2907; https://doi.org/10.3390/biomedicines12122907 - 20 Dec 2024
Viewed by 1002
Abstract
Background/Objectives: Some specific types of white blood cells (WBCs) and the neutrophil/lymphocyte ratio (NLR) are independent predictors of outcome for heart failure (HF) patients. WBC redistribution is induced by catecholamines, and therefore we evaluate how different types of beta-blockers (BBs) influence it. Methods: [...] Read more.
Background/Objectives: Some specific types of white blood cells (WBCs) and the neutrophil/lymphocyte ratio (NLR) are independent predictors of outcome for heart failure (HF) patients. WBC redistribution is induced by catecholamines, and therefore we evaluate how different types of beta-blockers (BBs) influence it. Methods: The HF patients were clinically evaluated, and blood was drawn to measure N-Terminal pro–B-type natriuretic peptide (NT-proBNP), WBC-differential formula, etc. Results: On admission, 61.16% of patients who used a BB had no significant difference in the number of lymphocytes (Lym) and neutrophils (Neu), but NLR and NT- proBNP were significantly lower compared with those without BB. NT-proBNP correlated with BB dose on admission and was significantly lower in patients treated with Metoprolol (Met) as compared with Carvedilol (Car). The type and dose of BB used was responsible for 6.1% and 5.9% of the variability in the number of Lym and Neu, respectively. Patients treated with ≥100 mg Met/day had a higher Lym number, but not of Neu, with reduced NLR, compared with lower doses. Patients treated with ≥25 mg Car/day had a lower Lym number and a greater Neu number, compared with lower doses, with increased NLR. Conclusions: However, both BBs had the same rehospitalization rate during the 12 month follow-up and had an improved outcome. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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12 pages, 2051 KiB  
Article
Cardiotoxic and Cardioprotective Effects of Methylene Blue in the Animal Model of Cardiac Ischemia and Reperfusion
by Hezio Jadir Fernandes Junior, Erisvaldo Amarante de Araújo, José Antônio Machado Junior, Fabio Marinho Lutz Motta, Gabriela Ferrazzano Guarize, Lucas Chen Cheng, Junaid Tantray, Jand Venes Rolim Medeiros, Lucas Antonio Duarte Nicolau, Adriano Henrique Pereira Barbosa, Adriano Caixeta, Isadora S. Rocco, Solange Guizilini, Marcelo Pires-Oliveira, Murched Omar Taha, Afonso Caricati-Neto, Walter José Gomes, Fernando Sabia Tallo and Francisco Sandro Menezes-Rodrigues
Biomedicines 2024, 12(11), 2575; https://doi.org/10.3390/biomedicines12112575 - 11 Nov 2024
Viewed by 1911
Abstract
Background/Objectives: Treatment of patients with myocardial ischemic diseases crucially involves cardiac reperfusion (CR). However, oxidative stress and tissue lesions caused by CR may also lead to lethal complications, such as arrythmias and vasoplegic syndrome (VS). Although methylene blue (MB) has long been used [...] Read more.
Background/Objectives: Treatment of patients with myocardial ischemic diseases crucially involves cardiac reperfusion (CR). However, oxidative stress and tissue lesions caused by CR may also lead to lethal complications, such as arrythmias and vasoplegic syndrome (VS). Although methylene blue (MB) has long been used to treat VS due to cardiac ischemia and reperfusion (CIR) and/or surgery because of its vascular effects, MB’s effects on the heart are unclear. Therefore, we investigated the potential cardioprotective or arrhythmogenic effects of MB in an animal model of CIR. To this end, 12–16-week-old male Wistar rats were divided into four experimental groups: (a) rats subjected to SHAM surgery with no ischemia; (b) rats subjected to CIR and treated with a vehicle (SS + CIR); and (c) rats subjected to CIR and treated with 2 mg/kg i.v. MB before ischemia (MB + ISQ) or (d) after ischemia but before reperfusion (ISQ + MB). An ECG analysis was used to evaluate the incidence of ventricular arrhythmias (VAs), atrioventricular blocks (AVBs), and lethality (LET) resulting from CIR. After CIR, rat hearts were removed for histopathological analysis and lipid hydroperoxide (LH) measurements. Results: The incidence of VA, AVB, and LET was significantly increased in the MB + ISQ group (VA = 100%; AVB = 100%; LET = 100%) but significantly reduced in the ISQ + MB group (VA = 42.8%; AVB = 28.5%; LET = 21.4%) compared with the SS + CIR group (VA = 85.7%; AVB = 71.4%; LET = 64.2%). LH concentration was significantly reduced in both MB-treated groups, but myocardial injuries were increased only in the MB + ISQ group when compared with the SS + CIR group. Conclusions: These results indicate that MB produces a biphasic effect on CIR, with cardiotoxic effects when administered before cardiac ischemia and cardioprotective effects when administered after ischemia but before cardiac reperfusion. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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17 pages, 10591 KiB  
Article
LncRNA Taurine Up-Regulated 1 Knockout Provides Neuroprotection in Ischemic Stroke Rats by Inhibiting Nuclear-Cytoplasmic Shuttling of HuR
by Xiaocheng Shi, Sha Liu, Yichun Zou, Hengping Wu, Jinyang Ma, Junbin Lin and Xin Zhang
Biomedicines 2024, 12(11), 2520; https://doi.org/10.3390/biomedicines12112520 - 4 Nov 2024
Viewed by 1254
Abstract
Background: Long non-coding RNA taurine-upregulated gene 1 (TUG1) is involved in various cellular processes, but its role in cerebral ischemia–reperfusion injury remains unclear. This study investigated TUG1’s role in regulating the nucleocytoplasmic shuttling of human antigen R (HuR), a key apoptosis regulator [...] Read more.
Background: Long non-coding RNA taurine-upregulated gene 1 (TUG1) is involved in various cellular processes, but its role in cerebral ischemia–reperfusion injury remains unclear. This study investigated TUG1’s role in regulating the nucleocytoplasmic shuttling of human antigen R (HuR), a key apoptosis regulator under ischemic conditions. Methods: CRISPR-Cas9 technology was used to generate TUG1 knockout Sprague Dawley rats to assess TUG1’s impact on ischemic injury. The infarct area and neuronal apoptosis were evaluated using TUNEL, hematoxylin and eosin (HE), and TTC staining, while behavioral functions were assessed. Immunofluorescence staining with confocal microscopy was employed to examine TUG1-mediated HuR translocation and expression changes in the apoptosis-related proteins COX-2 and Bax. Results: TUG1 knockout rats showed significantly reduced cerebral infarct areas, decreased neuronal apoptosis, and improved neurological functions compared to controls. Immunofluorescence staining revealed that HuR translocation from the nucleus to the cytoplasm was inhibited, leading to decreased COX-2 and Bax expression levels. Conclusions: TUG1 knockout reduces ischemic damage and neuronal apoptosis by inhibiting HuR nucleocytoplasmic shuttling, making TUG1 a potential therapeutic target for ischemic stroke. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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12 pages, 1249 KiB  
Article
Recovery from Acute Kidney Injury and Long-Term Prognosis following Acute Myocardial Infarction
by Keren Skalsky, Arthur Shiyovich, Alon Shechter, Harel Gilutz and Ygal Plakht
Biomedicines 2024, 12(7), 1490; https://doi.org/10.3390/biomedicines12071490 - 5 Jul 2024
Cited by 1 | Viewed by 1137
Abstract
We investigated the recovery pattern from acute kidney injury (AKI) following acute myocardial infarction (AMI) and its association with long-term mortality. The retrospective study included AMI patients (2002–2027), who developed AKI during hospitalization. Creatinine (Cr) measurements were collected and categorized into 24 h [...] Read more.
We investigated the recovery pattern from acute kidney injury (AKI) following acute myocardial infarction (AMI) and its association with long-term mortality. The retrospective study included AMI patients (2002–2027), who developed AKI during hospitalization. Creatinine (Cr) measurements were collected and categorized into 24 h timeframes up to 7 days from AKI diagnosis. The following groups of recovery patterns were defined: rapid (24–48 h)/no rapid and early (72–144 h)/no early recovery. Specific cut-off points for recovery at each AKI stage and timeframe were determined through receiver operating characteristic (ROC) curves. The probability of long-term (up to 10 years) mortality as a post-AKI recovery was investigated using a survival approach. Out of 17,610 AMI patients, 1069 developed AKI. For stage 1 AKI, patients with a Cr ratio <1.5 at 24 h and/or <1.45 at 48 h were defined as ‘rapid recovery’; for stages 2–3 AKI, a Cr ratio <2.5 at 96 h was defined as ‘early recovery’. Mortality risk in stage 1 AKI was higher among the non-rapidly recovered: AdjHR = 1.407; 95% CI: 1.086–1.824; p = 0.010. Among stages 2–3 AKI patients, the risk for long-term mortality was higher among patients who did not recover in the early period: AdjHR = 1.742; 95% CI: 1.085–2.797; p = 0.022. The absence of rapid recovery in stage 1 AKI and lack of early recovery in stages 2–3 AKI are associated with higher long-term mortality. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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15 pages, 3817 KiB  
Article
Effects of Lithium Ions on tPA-Induced Hemorrhagic Transformation under Stroke
by Valentina A. Babenko, Elmira I. Yakupova, Irina B. Pevzner, Alexey D. Bocharnikov, Ljubava D. Zorova, Kseniya S. Fedulova, Oleg A. Grebenchikov, Artem N. Kuzovlev, Andrey V. Grechko, Denis N. Silachev, Parvaneh Rahimi-Moghaddam and Egor Y. Plotnikov
Biomedicines 2024, 12(6), 1325; https://doi.org/10.3390/biomedicines12061325 - 14 Jun 2024
Viewed by 1375
Abstract
Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on [...] Read more.
Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on HT mechanisms are still unknown. In our study, we use the models of photothrombosis (PT)-induced brain ischemia and oxygen-glucose deprivation (OGD) to investigate the effect of Li+ on tPA-induced changes in brain and endothelial cell cultures. We found that tPA did not affect lesion volume or exacerbate neurological deficits but disrupted the blood–brain barrier. We demonstrate that poststroke treatment with Li+ improves neurological status and increases blood–brain barrier integrity after thrombolytic therapy. Under conditions of OGD, tPA treatment increased MMP-2/9 levels in endothelial cells, and preincubation with LiCl abolished this MMP activation. Moreover, we observed the effect of Li+ on glycolysis in tPA-treated endothelial cells, which we hypothesized to have an effect on MMP expression. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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Review

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19 pages, 1709 KiB  
Review
Exploring RNF213 in Ischemic Stroke and Moyamoya Disease: From Cellular Models to Clinical Insights
by Benjamin Y. Q. Tan, Charlene H. P. Kok, Megan B. J. Ng, Shaun Loong, Eric Jou, Leonard L. L. Yeo, Weiping Han, Christopher D. Anderson, Chiea Chuen Khor and Poh San Lai
Biomedicines 2025, 13(1), 17; https://doi.org/10.3390/biomedicines13010017 - 26 Dec 2024
Viewed by 1778
Abstract
Advances in stroke genetics have highlighted the critical role of rare genetic variants in cerebrovascular diseases, with RNF213 emerging as a key player in ischemic stroke and Moyamoya disease (MMD). Initially identified as the primary susceptibility gene for MMD, RNF213—notably the p.R4810K [...] Read more.
Advances in stroke genetics have highlighted the critical role of rare genetic variants in cerebrovascular diseases, with RNF213 emerging as a key player in ischemic stroke and Moyamoya disease (MMD). Initially identified as the primary susceptibility gene for MMD, RNF213—notably the p.R4810K variant—has been strongly linked to intracranial artery stenosis (ICAS) and various ischemic stroke subtypes, particularly in East Asian populations. This gene encodes an E3 ubiquitin ligase with diverse roles in angiogenesis, vascular remodeling, lipid metabolism, and cerebral blood flow regulation, yet its exact mechanisms in cerebrovascular pathology remain incompletely understood. This review synthesizes findings from genetic studies, as well as cellular and animal models, to provide a holistic understanding of RNF213’s involvement in cerebrovascular diseases. Key mechanisms by which RNF213 variants contribute to disease pathogenesis are explored, alongside discussions on their clinical utility as biomarkers and therapeutic targets. Additionally, we address the gene’s implications for disease prediction, risk assessment, and cascade screening. By integrating evidence across disciplines, this review identifies critical knowledge gaps, including the biological pathways underlying RNF213’s pathogenicity. These insights lay the groundwork for future research and underscore the potential of RNF213 in driving personalized approaches to cerebrovascular disease management. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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23 pages, 1946 KiB  
Review
Gut Microbiota, Bacterial Translocation, and Stroke: Current Knowledge and Future Directions
by Cristina Granados-Martinez, Nuria Alfageme-Lopez, Manuel Navarro-Oviedo, Carmen Nieto-Vaquero, Maria Isabel Cuartero, Blanca Diaz-Benito, Maria Angeles Moro, Ignacio Lizasoain, Macarena Hernandez-Jimenez and Jesus Miguel Pradillo
Biomedicines 2024, 12(12), 2781; https://doi.org/10.3390/biomedicines12122781 - 6 Dec 2024
Cited by 1 | Viewed by 1649
Abstract
Stroke is one of the most devastating pathologies in terms of mortality, cause of dementia, major adult disability, and socioeconomic burden worldwide. Despite its severity, treatment options remain limited, with no pharmacological therapies available for hemorrhagic stroke (HS) and only fibrinolytic therapy or [...] Read more.
Stroke is one of the most devastating pathologies in terms of mortality, cause of dementia, major adult disability, and socioeconomic burden worldwide. Despite its severity, treatment options remain limited, with no pharmacological therapies available for hemorrhagic stroke (HS) and only fibrinolytic therapy or mechanical thrombectomy for ischemic stroke (IS). In the pathophysiology of stroke, after the acute phase, many patients develop systemic immunosuppression, which, combined with neurological dysfunction and hospital management, leads to the onset of stroke-associated infections (SAIs). These infections worsen prognosis and increase mortality. Recent evidence, particularly from experimental studies, has highlighted alterations in the microbiota–gut–brain axis (MGBA) following stroke, which ultimately disrupts the gut flora and increases intestinal permeability. These changes can result in bacterial translocation (BT) from the gut to sterile organs, further contributing to the development of SAIs. Given the novelty and significance of these processes, especially the role of BT in the development of SAIs, this review summarizes the latest advances in understanding these phenomena and discusses potential therapeutic strategies to mitigate them, ultimately reducing post-stroke complications and improving treatment outcomes. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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23 pages, 844 KiB  
Review
Reversal of Atherosclerotic Plaque Growth and Vulnerability: Effects of Lipid-Modifying and Anti-Inflammatory Therapeutic Agents
by Michail I. Papafaklis, Rafail Koros, Grigorios Tsigkas, Antonios Karanasos, Athanasios Moulias and Periklis Davlouros
Biomedicines 2024, 12(11), 2435; https://doi.org/10.3390/biomedicines12112435 - 23 Oct 2024
Cited by 3 | Viewed by 4325
Abstract
Atherosclerotic plaque development constitutes the primary substrate of coronary artery disease (CAD) and is the outcome of an intricate process involving endothelial damage, inflammation, and lipid retention. The clinical efficacy of many lipid-lowering therapies in patients with CAD has been well established. Over [...] Read more.
Atherosclerotic plaque development constitutes the primary substrate of coronary artery disease (CAD) and is the outcome of an intricate process involving endothelial damage, inflammation, and lipid retention. The clinical efficacy of many lipid-lowering therapies in patients with CAD has been well established. Over the past few decades, a substantial and significant advance regarding the use of invasive and non-invasive imaging modalities has been observed. Numerous studies have been conducted using these imaging techniques and have investigated the changes in morphology (e.g., atheroma volume) and composition (e.g., lipid burden, fibrous cap thickness, macrophage accumulation) at the plaque level that explain the improved clinical outcomes by various pharmacological interventions. Lipid-lowering agents, such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, demonstrate direct effects on plaque volume and composition that enhance plaque stabilization and/or regression beyond the reduction of low-density lipoproteins. An increasing amount of clinical research is also focused on the role of inflammation in plaque vulnerability and future adverse cardiac events. Consequently, there is a pressing need to explore therapeutic strategies that are capable of disrupting the inflammatory response as well as reducing atheroma burden and modifying high-risk plaque characteristics. This review provides a comprehensive analysis of the current evidence regarding the effects of traditional and novel therapeutic strategies targeting modification of the lipid profile and inflammatory processes on reversing plaque growth and attenuating vulnerable features, thereby promoting plaque stabilization and passivation. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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18 pages, 803 KiB  
Review
Differential Role of Factor XIII in Acute Myocardial Infarction and Ischemic Stroke
by Jan Traub, Martin S. Weber and Anna Frey
Biomedicines 2024, 12(3), 497; https://doi.org/10.3390/biomedicines12030497 - 22 Feb 2024
Cited by 2 | Viewed by 2133
Abstract
Factor XIII is a transglutaminase enzyme that plays a crucial role in hemostasis and wound healing. It crosslinks fibrin strands, stabilizing clots and promoting clot resistance to fibrinolysis. Additionally, Factor XIII has been found to have multiple other functions that extend beyond coagulation, [...] Read more.
Factor XIII is a transglutaminase enzyme that plays a crucial role in hemostasis and wound healing. It crosslinks fibrin strands, stabilizing clots and promoting clot resistance to fibrinolysis. Additionally, Factor XIII has been found to have multiple other functions that extend beyond coagulation, including the regulation of inflammation and tissue repair processes. Emerging evidence suggests that Factor XIII may also have differential roles in acute myocardial infarction and ischemic stroke, two common cardiovascular events with significant morbidity and mortality. In acute myocardial infarction, Factor XIII has been implicated in promoting clot stability and reducing the risk of re-occlusion. In ischemic stroke, Factor XIII may also contribute to the pathogenesis of cerebral ischemia by promoting clot formation and exacerbating neuronal damage. Several studies have investigated the association between Factor XIII and these cardiovascular events, using various approaches such as genetic polymorphism analysis, animal models, and clinical data analysis. These studies have provided important insights into the role of Factor XIII in acute myocardial infarction and ischemic stroke, highlighting its potential as a therapeutic target for interventions aimed at improving outcomes in these conditions. In this review, we will summarize the current understanding of Factor XIII’s role in acute myocardial infarction and ischemic stroke. Full article
(This article belongs to the Special Issue Ischemic Stroke and Myocardial Infarction: Potential Therapeutic Targets and Translational Research)
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