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Advanced Healthcare Materials Aug 2023Myocardial ischemic/reperfusion (IR) injury is a global cardiovascular disease with high mortality and morbidity. Therapeutic interventions for myocardial ischemia... (Review)
Review
Myocardial ischemic/reperfusion (IR) injury is a global cardiovascular disease with high mortality and morbidity. Therapeutic interventions for myocardial ischemia involve restoring the occluded coronary artery. However, reactive oxygen species (ROS) inevitably impair the cardiomyocytes during the ischemic and reperfusion phases. Antioxidant therapy holds great promise against myocardial IR injury. The current therapeutic methodologies for ROS scavenging depend predominantly on administering antioxidants. Nevertheless, the intrinsic drawbacks of antioxidants limit their further clinical transformation. The use of nanoplatforms with versatile characteristics greatly benefits drug delivery in myocardial ischemic therapy. Nanoplatform-mediated drug delivery significantly improves drug bioavailability, increases therapeutic index, and reduces systemic toxicity. Nanoplatforms can be specifically and reasonably designed to enhance molecule accumulation at the myocardial site. The present review initially summarizes the mechanism of ROS generation during the process of myocardial ischemia. The understanding of this phenomenon will facilitate the advancement of innovative therapeutic strategies against myocardial IR injury. The latest developments in nanomedicine for treating myocardial ischemic injury are then discussed. Finally, the current challenges and perspectives in antioxidant therapy for myocardial IR injury are addressed.
Topics: Humans; Myocardial Reperfusion Injury; Antioxidants; Reactive Oxygen Species; Nanomedicine; Myocardial Ischemia; Reperfusion Injury
PubMed: 36971662
DOI: 10.1002/adhm.202300161 -
Cellular and Molecular Life Sciences :... Oct 2023Following myocardial ischemic injury, the most effective clinical intervention is timely restoration of blood perfusion to ischemic but viable myocardium to reduce... (Review)
Review
Following myocardial ischemic injury, the most effective clinical intervention is timely restoration of blood perfusion to ischemic but viable myocardium to reduce irreversible myocardial necrosis, limit infarct size, and prevent cardiac insufficiency. However, reperfusion itself may exacerbate cell death and myocardial injury, a process commonly referred to as ischemia/reperfusion (I/R) injury, which primarily involves cardiomyocytes and cardiac microvascular endothelial cells (CMECs) and is characterized by myocardial stunning, microvascular damage (MVD), reperfusion arrhythmia, and lethal reperfusion injury. MVD caused by I/R has been a neglected problem compared to myocardial injury. Clinically, the incidence of microvascular angina and/or no-reflow due to ineffective coronary perfusion accounts for 5-50% in patients after acute revascularization. MVD limiting drug diffusion into injured myocardium, is strongly associated with the development of heart failure. CMECs account for > 60% of the cardiac cellular components, and their role in myocardial I/R injury cannot be ignored. There are many studies on microvascular obstruction, but few studies on microvascular leakage, which may be mainly due to the lack of corresponding detection methods. In this review, we summarize the clinical manifestations, related mechanisms of MVD during myocardial I/R, laboratory and clinical examination means, as well as the research progress on potential therapies for MVD in recent years. Better understanding the characteristics and risk factors of MVD in patients after hemodynamic reconstruction is of great significance for managing MVD, preventing heart failure and improving patient prognosis.
Topics: Humans; Endothelial Cells; Myocardial Infarction; Myocardium; Myocardial Reperfusion Injury; Heart Failure
PubMed: 37898977
DOI: 10.1007/s00018-023-04998-z -
Biomaterials Dec 2023Reperfusion therapy is widely used to treat acute myocardial infarction. However, its efficacy is limited by myocardial ischemia-reperfusion injury (MIRI), which occurs... (Review)
Review
Reperfusion therapy is widely used to treat acute myocardial infarction. However, its efficacy is limited by myocardial ischemia-reperfusion injury (MIRI), which occurs paradoxically due to the reperfusion therapy and contributes to the high mortality rate of acute myocardial infarction. Systemic administration of drugs, such as antioxidant and anti-inflammatory agents, to reduce MIRI is often ineffective due to the inadequate release at the pathological sites. Functional biomaterials are being developed to optimize the use of drugs by improving their targetability and bioavailability and reducing side effects, such as gastrointestinal irritation, thrombocytopenia, and liver damage. This review provides an overview of controlled drug delivery biomaterials for treating MIRI by triggering antioxidation, calcium ion overload inhibition, and/or inflammation regulation mechanisms and discusses the challenges and potential applications of these treatments clinically.
Topics: Humans; Myocardial Reperfusion Injury; Antioxidants; Myocardial Infarction
PubMed: 37977009
DOI: 10.1016/j.biomaterials.2023.122368 -
The American Journal of the Medical... Sep 2023Myocardial ischemia-reperfusion injury (MIRI) is a serious complication affecting the prognosis of patients with myocardial infarction and can cause cardiac arrest,... (Review)
Review
Myocardial ischemia-reperfusion injury (MIRI) is a serious complication affecting the prognosis of patients with myocardial infarction and can cause cardiac arrest, reperfusion arrhythmias, no-reflow, and irreversible myocardial cell death. Ferroptosis, an iron-dependent, peroxide-driven, non-apoptotic form of regulated cell death, plays a vital role in reperfusion injury. Acetylation, an important post-translational modification, participates in many cellular signaling pathways and diseases, and plays a pivotal role in ferroptosis. Elucidating the role of acetylation in ferroptosis may therefore provide new insights for the treatment of MIRI. Here, we summarized the recently discovered knowledge about acetylation and ferroptosis in MIRI. Finally, we focused on the acetylation modification during ferroptosis and its potential relationship with MIRI.
Topics: Humans; Myocardial Reperfusion Injury; Ferroptosis; Acetylation; Myocardium; Protein Processing, Post-Translational
PubMed: 37290744
DOI: 10.1016/j.amjms.2023.04.034 -
American Journal of Cardiovascular... Jan 2024Acute myocardial infarction (AMI) is associated with high morbidity and mortality worldwide. Although early reperfusion is the most effective strategy to salvage... (Review)
Review
Acute myocardial infarction (AMI) is associated with high morbidity and mortality worldwide. Although early reperfusion is the most effective strategy to salvage ischemic myocardium, reperfusion injury can develop with the restoration of blood flow. Therefore, it is important to identify protection mechanisms and strategies for the heart after myocardial infarction. Recent studies have shown that multiple intracellular molecules and signaling pathways are involved in cardioprotection. Meanwhile, device-based cardioprotective modalities such as cardiac left ventricular unloading, hypothermia, coronary sinus intervention, supersaturated oxygen (SSO), and remote ischemic conditioning (RIC) have become important areas of research. Herein, we review the molecular mechanisms of cardioprotection and cardioprotective modalities after ischemia-reperfusion injury (IRI) to identify potential approaches to reduce mortality and improve prognosis in patients with AMI.
Topics: Humans; Myocardial Reperfusion Injury; Myocardial Infarction; Heart; Signal Transduction
PubMed: 37815758
DOI: 10.1007/s40256-023-00614-4 -
Basic Research in Cardiology Oct 2023The spleen contributes importantly to myocardial ischemia/reperfusion (MI/R) injury. Nucleotide-binding oligomerization domain-like receptor family pyrin domain...
The spleen contributes importantly to myocardial ischemia/reperfusion (MI/R) injury. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) recruits inflammasomes, initiating inflammatory responses and mediating tissue injury. We hypothesize that myocardial cell-free DNA (cfDNA) activates the splenic NLRP3 inflammasome during early reperfusion, increases systemic inflammatory response, and exacerbates myocardial infarct. Mice were subjected to 40 min of ischemia followed by 0, 1, 5, or 15 min, or 24 h of reperfusion. Splenic leukocyte adoptive transfer was performed by injecting isolated splenocytes to mice with splenectomy performed prior to left coronary artery occlusion. CY-09 (4 mg/kg) was administered 5 min before reperfusion. During post-ischemic reperfusion, splenic protein levels of NLRP3, cleaved caspase-1, and interleukin-1β (IL-1β) were significantly elevated and peaked (2.1 ± 0.2-, 3.4 ± 0.4-, and 3.2 ± 0.2-fold increase respectively, p < 0.05) within 5 min of reperfusion. In myocardial tissue, NLRP3 was not upregulated until 24 h after reperfusion. Suppression by CY09, a specific NLRP3 inflammasome inhibitor, or deficiency of NLRP3 significantly reduced myocardial infarct size (17.3% ± 4.2% and 33.2% ± 1.8% decrease respectively, p < 0.01). Adoptive transfer of NLRP3 splenocytes to WT mice significantly decreased infarct size compared to transfer of WT splenocytes (19.1% ± 2.8% decrease, p < 0.0001). NLRP3 was mainly activated at 5 min after reperfusion in CD11b and LY6G splenocytes, which significantly increased during reperfusion (24.8% ± 0.7% vs.14.3% ± 0.6%, p < 0.0001). The circulating cfDNA level significantly increased in patients undergoing cardiopulmonary bypass (CPB) (43.3 ± 5.3 ng/mL, compared to pre-CPB 23.8 ± 3.5 ng/mL, p < 0.01). Mitochondrial cfDNA (mt-cfDNA) contributed to NLRP3 activation in macrophages (2.1 ± 0.2-fold increase, p < 0.01), which was inhibited by a Toll-like receptor 9(TLR9) inhibitor. The NLRP3 inflammasome in splenic monocytes is activated and mediates the inflammatory response shortly after reperfusion onset, exacerbating MI/R injury in mt-cfDNA/TLR9-dependent fashion. The schema reveals splenic NLRP3 mediates the inflammatory response in macrophages and exacerbates MI/R in a mitochondrial cfDNA/ TLR9-dependent fashion.
Topics: Humans; Mice; Animals; Myocardial Reperfusion Injury; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Monocytes; Toll-Like Receptor 9; Spleen; Cell-Free Nucleic Acids; Myocardial Infarction; Reperfusion Injury
PubMed: 37814087
DOI: 10.1007/s00395-023-01014-0 -
PloS One 2023Recently, myocardial ischemia-reperfusion (I/R) injury was suggested associated with intestinal flora. However, irisin has demonstrated beneficial effects on myocardial...
Recently, myocardial ischemia-reperfusion (I/R) injury was suggested associated with intestinal flora. However, irisin has demonstrated beneficial effects on myocardial I/R injury, thus increasing interest in exploring its mechanism. Therefore, whether irisin interferes in gut microbiota and gut mucosal barrier during myocardial I/R injury was investigated in the present study. Irisin was found to reduce the infiltration of inflammatory cells and fracture in myocardial tissue, myocardial enzyme levels, and the myocardial infarction (MI) area. In addition, the data showed that irisin reverses I/R-induced gut dysbiosis as indicated by the decreased abundance of Actinobacteriota and the increased abundance of Firmicutes, and maintains intestinal barrier integrity, reduces metabolic endotoxemia, and inhibits the production of proinflammatory cytokines interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α). Based on the results, irisin could be a good candidate for ameliorating myocardial I/R injury and associated diseases by alleviating gut dysbiosis, endothelial dysfunction and anti-inflammatory properties.
Topics: Animals; Rats; Fibronectins; Gastrointestinal Microbiome; Dysbiosis; Myocardial Reperfusion Injury; Interleukin-6; Permeability
PubMed: 37656700
DOI: 10.1371/journal.pone.0291022 -
International Journal of Molecular... Apr 2024Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate... (Review)
Review
Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.
Topics: Humans; Signal Transduction; Animals; Myocardial Reperfusion Injury; Mitochondria, Heart; Protein Kinases; Reactive Oxygen Species; Mitochondria
PubMed: 38674076
DOI: 10.3390/ijms25084491 -
Genes & Diseases Nov 2023Autophagy is an evolutionarily conserved process involved in the degradation of long-lived proteins and excessive or dysfunctional organelles. As a pivotal cellular... (Review)
Review
Autophagy is an evolutionarily conserved process involved in the degradation of long-lived proteins and excessive or dysfunctional organelles. As a pivotal cellular response, autophagy has been extensively studied and is known to be involved in various diseases. Ferroptosis is a recently discovered form of regulated cell death characterized by iron overload, leading to the accumulation of lethal levels of lipid hydroperoxides. Recently, an increasing number of studies have revealed a link between autophagy and ferroptosis. Myocardial ischemia/reperfusion injury (MIRI) is an urgent dilemma after myocardial infarction recanalization, which is regulated by several cell death pathways, including autophagy and ferroptosis. However, the potential relationship between autophagy and ferroptosis in MIRI remains unexplored. In this study, we briefly review the mechanisms of autophagy and ferroptosis, including their roles in MIRI. Moreover, we provide an overview of the potential crosstalk in MIRI. Clarifying the relationship between different cell death pathways may provide new ideas for the treatment of MIRI in the future.
PubMed: 37554184
DOI: 10.1016/j.gendis.2022.02.012 -
Theranostics 2024The transition from acute inflammation to fibrosis following myocardial ischemia‒reperfusion (MIR) significantly affects prognosis. Macrophages play a pivotal role in...
The transition from acute inflammation to fibrosis following myocardial ischemia‒reperfusion (MIR) significantly affects prognosis. Macrophages play a pivotal role in inflammatory damage and repair after MIR. However, the heterogeneity and transformation mechanisms of macrophages during this transition are not well understood. In this study, we used single-cell RNA sequencing (scRNA-seq) and mass cytometry to examine murine monocyte-derived macrophages after MIR to investigate macrophage subtypes and their roles in the MIR process. S100a9 mice were used to establish MIR model to clarify the mechanism of alleviating inflammation and fibrosis after MIR. Reinfusion of bone marrow-derived macrophages (BMDMs) after macrophage depletion (MD) in mice subjected to MIR were performed to further examine the role of S100a9 macrophages in MIR. We identified a unique subtype of S100a9 macrophages that originate from monocytes and are involved in acute inflammation and fibrosis. These S100a9 macrophages infiltrate the heart as early as 2 h post-reperfusion and activate the Myd88/NFκB/NLRP3 signaling pathway, amplifying inflammatory responses. As the tissue environment shifts from proinflammatory to reparative, S100a9 activates transforming growth factor-β (Tgf-β)/p-smad3 signaling. This activation not only induces the transformation of myocardial fibroblasts to myofibroblasts but also promotes fibrosis via the macrophage-to-myofibroblast transition (MMT). Targeting S100a9 with a specific inhibitor could effectively mitigate acute inflammatory damage and halt the progression of fibrosis, including MMT. S100a9 macrophages are a promising therapeutic target for managing the transition from inflammation to fibrosis after MIR.
Topics: Mice; Animals; Macrophages; Myocardial Reperfusion Injury; Fibrosis; Inflammation; Coronary Artery Disease; Ischemia; Reperfusion; Sequence Analysis, RNA; Mice, Inbred C57BL
PubMed: 38323308
DOI: 10.7150/thno.91180