-
JCI Insight Mar 2024Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and...
Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.
Topics: Mice; Animals; Phagocytosis; Efferocytosis; Apoptosis; Macrophages; Inflammation; Membrane Proteins; Myocardial Reperfusion Injury; Reperfusion
PubMed: 38456501
DOI: 10.1172/jci.insight.173832 -
European Journal of Pharmacology Jul 2023Intramyocardial hemorrhage (IMH), a reperfusion therapy-associated complication, is the extravasation of red blood cells caused by severe microvascular injury. IMH is an...
Intramyocardial hemorrhage (IMH), a reperfusion therapy-associated complication, is the extravasation of red blood cells caused by severe microvascular injury. IMH is an independent predictor of adverse ventricular remodeling (AVR) after acute myocardial infarction (AMI). Hepcidin, a major regulator of iron uptake and systemic distribution, is a key factor affecting AVR. However, the role of cardiac hepcidin in the development of IMH has not been completely elucidated. This study aimed to explore if sodium-dependent glucose co-transporter 2 inhibitor (SGLT2i) exerts therapeutic effects on IMH and AVR by suppressing hepcidin and to elucidate the underlying mechanisms. SGLT2i alleviated IMH and AVR in the ischemia-reperfusion injury (IRI) mouse model. Additionally, SGLT2i downregulated the cardiac levels of hepcidin in IRI mice, suppressed M1-type macrophage polarization, and promoted M2-type macrophage polarization. The effects of hepcidin knockdown on macrophage polarization were similar to those of SGLT2i in RAW264.7 cells. SGLT2i treatment or hepcidin knockdown inhibited the expression of MMP9, an inducer of IMH and AVR, in RAW264.7 cells. Regulation of macrophage polarization and reduction of MMP9 expression by SGLT2i and hepcidin knockdown is achieved through activation of pSTAT3. In conclusion, this study demonstrated that SGLT2i alleviated IMH and AVR by regulating macrophage polarization. The potential mechanism through which SGLT2i exerted its therapeutic effect seems to involve the downregulation of MMP9 via the hepcidin-STAT3 pathway.
Topics: Mice; Animals; Myocardial Reperfusion Injury; Sodium-Glucose Transporter 2 Inhibitors; Matrix Metalloproteinase 9; Ventricular Remodeling; Hepcidins; Hemorrhage
PubMed: 37100110
DOI: 10.1016/j.ejphar.2023.175729 -
Neurocritical Care Feb 2024
Topics: Humans; Brain Edema; Stroke; Brain Ischemia; Thrombectomy; Reperfusion; Treatment Outcome; Retrospective Studies; Endovascular Procedures
PubMed: 38148434
DOI: 10.1007/s12028-023-01901-3 -
IScience Sep 2023Morbidity and mortality caused by acute myocardial infarction (AMI) are on the rise, posing a grave threat to the health of the general population. Up to now,... (Review)
Review
Morbidity and mortality caused by acute myocardial infarction (AMI) are on the rise, posing a grave threat to the health of the general population. Up to now, interventional, surgical, and pharmaceutical therapies have been the main treatment methods for AMI. Effective and timely reperfusion therapy decreases mortality, but it cannot stimulate myocardial cell regeneration or reverse ventricular remodeling. Cell therapy, gene therapy, immunotherapy, anti-inflammatory therapy, and several other techniques are utilized by researchers to improve patients' prognosis. In recent years, biomaterials for AMI therapy have become a hot spot in medical care. Biomaterials furnish a microenvironment conducive to cell growth and deliver therapeutic factors that stimulate cell regeneration and differentiation. Biomaterials adapt to the complex microenvironment and respond to changes in local physical and biochemical conditions. Therefore, environmental factors and material properties must be taken into account when designing biomaterials for the treatment of AMI. This article will review the factors that need to be fully considered in the design of biological materials.
PubMed: 37670787
DOI: 10.1016/j.isci.2023.107662 -
Phytomedicine : International Journal... Nov 2023The urgent challenge for ischemic stroke treatment is the lack of effective neuroprotectants that target multiple pathological processes. Crebanine, an isoquinoline-like...
BACKGROUND
The urgent challenge for ischemic stroke treatment is the lack of effective neuroprotectants that target multiple pathological processes. Crebanine, an isoquinoline-like alkaloid with superior pharmacological activities, presents itself as a promising candidate for neuroprotection. However, its effects and mechanisms on ischemic stroke remain unknown.
METHODS
The effects of crebanine on brain damage following ischemic stroke were evaluated using the middle cerebral artery occlusion and reperfusion (MCAO/R) model. Mechanism of action was investigated using both MCAO/R rats and lipopolysaccharide (LPS)-activated BV-2 cells.
RESULTS
We initially demonstrated that crebanine effectively ameliorated the neurological deficits in MCAO/R rats, while also reducing brain edema and infarction. Treatment with crebanine resulted in the up-regulation of NeuN fluorescence density and down-regulation of FJB cell count, and mitigated synaptic damage. Crebanine attenuated the hyperactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) by downregulating NADP+ and NADPH levels, suppressing gp91 and p47 expressions, and reducing p47 membrane translocation in Iba-1 cells. Additionally, crebanine reduced the quantity of Iba-1 cells and protein expression. Correlation analysis has demonstrated that the inhibition of NOX2 activation in microglia is beneficial for mitigating I/R brain injuries. Moreover, crebanine exhibited significant antioxidant properties by down-regulating the expression of superoxide anion and intracellular reactive oxygen species in vivo and in vitro, and reducing lipid and DNA peroxidation. Crebanine exerted anti-inflammatory effect, as evidenced by the reduction in the expressions of nitric oxide, interleukin 1β, tumor necrosis factor α, interleukin 6, and inducible nitric oxide synthase. The effect of crebanine was achieved through the suppression of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathway. This is supported by evidence showing reduced NF-κB p65 promoter activity and nucleus translocation, as well as suppressed IκBα phosphorylation and degradation. Additionally, it inhibited the phosphorylation of ERK, JNK, and p38 MAPKs. Importantly, the anti-oxidative stress and neuroinflammation effects of crebanine were further enhanced after silencing gp91 and p47.
CONCLUSION
Crebanine alleviated the brain damages of MCAO/R rats by inhibiting oxidative stress and neuroinflammation mediated by NOX2 in microglia, implying crebanine might be a potential natural drug for the treatment of cerebral ischemia.
Topics: Rats; Animals; NF-kappa B; Microglia; NADPH Oxidase 2; Neuroinflammatory Diseases; NADP; NADPH Oxidases; Oxidative Stress; Brain Ischemia; Infarction, Middle Cerebral Artery; Brain; Ischemic Stroke; Reperfusion
PubMed: 37634486
DOI: 10.1016/j.phymed.2023.155044 -
Revista Da Associacao Medica Brasileira... 2023Cerebrovascular accident (or stroke) and ischemic heart disease are the the major causes of death in the world. It is estimated that about 85% of strokes are ischemic in... (Observational Study)
Observational Study
BACKGROUND
Cerebrovascular accident (or stroke) and ischemic heart disease are the the major causes of death in the world. It is estimated that about 85% of strokes are ischemic in origin. Reperfusion therapy in the acute phase of ischemic stroke with a recombinant human tissue plasminogen activator is effective, but some factors influence the success of this treatment.
OBJECTIVE
The aim of this study was to evaluate clinical aspects and possible determinants for reperfusion after venous thrombolysis.
METHODS
This is a retrospective, cross-sectional, observational study based on a review of hospital records of inpatients diagnosed with ischemic stroke treated with intravenous thrombolysis, the main outcome being reperfusion or not.
RESULTS
Data from this study revealed a predominance of females in the group of reperfused patients and males in the non-reperfused group, both maintaining moderate severity on the National Institutes of Health Stroke Scale and admission without statistical significance (p>0.18). In addition, the mean admission severity score was 13.2 for the group of reperfused patients and 14.2 for those not reperfused, and the mean ejection fraction of both groups was within normal functionality, with a mean of 0.50 for reperfused patients and 0.62 for non-reperfused patients.
CONCLUSION
We found an association between successful venous chemical thrombolysis reperfusion and lower mortality in patients with acute stroke.
Topics: Female; Humans; Male; Brain Ischemia; Cross-Sectional Studies; Ischemic Stroke; Observational Studies as Topic; Reperfusion; Retrospective Studies; Stroke; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 38126448
DOI: 10.1590/1806-9282.20230472 -
Fundamental & Clinical Pharmacology Dec 2023The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain... (Review)
Review
The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain function, leading to the occurrence and development of cerebral ischemia/reperfusion (I/R) injury. Abundant evidence supports that metabolic defects of brain energy during the post-reperfusion period, especially low glucose oxidative metabolism and elevated glycolysis levels, which play a crucial role in cerebral I/R pathophysiology. Whereas research on brain energy metabolism dysfunction under the background of cerebral I/R mainly focuses on neurons, the research on the complexity of microglia energy metabolism in cerebral I/R is just emerging. As resident immune cells of the central nervous system, microglia activate rapidly and then transform into an M1 or M2 phenotype to correspond to changes in brain homeostasis during cerebral I/R injury. M1 microglia release proinflammatory factors to promote neuroinflammation, while M2 microglia play a neuroprotective role by secreting anti-inflammatory factors. The abnormal brain microenvironment promotes the metabolic reprogramming of microglia, which further affects the polarization state of microglia and disrupts the dynamic equilibrium of M1/M2, resulting in the aggravation of cerebral I/R injury. Increasing evidence suggests that metabolic reprogramming is a key driver of microglial inflammation. For example, M1 microglia preferentially produce energy through glycolysis, while M2 microglia provide energy primarily through oxidative phosphorylation. In this review, we highlight the emerging significance of regulating microglial energy metabolism in cerebral I/R injury.
Topics: Humans; Microglia; Brain Ischemia; Brain; Inflammation; Reperfusion Injury; Brain Diseases; Reperfusion
PubMed: 37339781
DOI: 10.1111/fcp.12928 -
CNS Neuroscience & Therapeutics Apr 2024Reperfusion therapy after ischemic stroke often causes brain microvascular injury. However, the underlying mechanisms are unclear.
BACKGROUND
Reperfusion therapy after ischemic stroke often causes brain microvascular injury. However, the underlying mechanisms are unclear.
METHODS
Transcriptomic and proteomic analyses were performed on human cerebral microvascular endothelial cells following oxygen-glucose deprivation (OGD) or OGD plus recovery (OGD/R) to identify molecules and signaling pathways dysregulated by reperfusion. Major findings were further validated in a mouse model of cerebral ischemia and reperfusion.
RESULTS
Transcriptomic analysis identified 390 differentially expressed genes (DEGs) between the OGD/R and OGD group. Pathway analysis indicated that these genes were mostly associated with inflammation, including the TNF signaling pathway, TGF-β signaling pathway, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and NF-κB signaling pathway. Proteomic analysis identified 201 differentially expressed proteins (DEPs), which were primarily associated with extracellular matrix destruction and remodeling, impairment of endothelial transport function, and inflammatory responses. Six genes (DUSP1, JUNB, NFKBIA, NR4A1, SERPINE1, and THBS1) were upregulated by OGD/R at both the mRNA and protein levels. In mice with cerebral ischemia and reperfusion, brain TNF signaling pathway was activated by reperfusion, and inhibiting TNF-α with adalimumab significantly attenuated reperfusion-induced brain endothelial inflammation. In addition, the protein level of THBS1 was substantially upregulated upon reperfusion in brain endothelial cells and the peri-endothelial area in mice receiving cerebral ischemia.
CONCLUSION
Our study reveals the key molecular signatures of brain endothelial reperfusion injury and provides potential therapeutic targets for the treatment of brain microvascular injury after reperfusion therapy in ischemic stroke.
Topics: Mice; Humans; Animals; Endothelial Cells; Proteomics; Brain; Brain Ischemia; Reperfusion Injury; Oxygen; Brain Injuries; Inflammation; Reperfusion; Gene Expression Profiling; Ischemic Stroke; Glucose
PubMed: 37789643
DOI: 10.1111/cns.14483 -
ACS Applied Materials & Interfaces Aug 2023Ischemia/reperfusion (I/R) injury causes excessive oxidative events and initiates destructive inflammatory responses, and it is an important promoter to the pathology of...
Ischemia/reperfusion (I/R) injury causes excessive oxidative events and initiates destructive inflammatory responses, and it is an important promoter to the pathology of various pathema states. Ferroptosis is an iron-dependent type of nonapoptotic cell death accompanied by the accumulation of membrane lipid peroxide and consumption of polyunsaturated fatty acid, and it plays a key role in I/R injury diseases. Moreover, the excessive production of inflammatory cytokines contributes to the development of acute kidney injury. Here, we reported neutrophil membrane-coated copper-based nanoparticles (N-CuO@DFO NPs) for I/R kidney injury treatment. The highly biocompatible and stable N-CuO@DFO NPs showed excellent antioxidant and iron ion scavenging abilities . Our finding showed that the N-CuO@DFO NPs strategy could significantly accumulate in the inflammatory kidney, reduce oxidative damage events and inflammatory response, and finally achieve synergistic therapy against renal I/R injury. This work promotes the development of nanoantioxidant agents with multiple antioxidant properties for the therapy of other I/R injury diseases.
Topics: Humans; Antioxidants; Copper; Neutrophils; Acute Kidney Injury; Kidney; Reperfusion Injury; Ischemia; Reperfusion; Iron
PubMed: 37603686
DOI: 10.1021/acsami.3c08573 -
Fundamental & Clinical Pharmacology Dec 2023The use of percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is associated with a mortality rate of 5%-7%. It... (Review)
Review
BACKGROUND
The use of percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is associated with a mortality rate of 5%-7%. It is clear that there is an urgent need to develop new drugs that can effectively prevent cardiac reperfusion injury. ATP-sensitive K (K ) channel openers (KCOs) can be classified as such drugs.
RESULTS
KCOs prevent irreversible ischemia and reperfusion injury of the heart. K channel opening promotes inhibition of apoptosis, necroptosis, pyroptosis, and stimulation of autophagy. KCOs prevent the development of cardiac adverse remodeling and improve cardiac contractility in reperfusion. KCOs exhibit antiarrhythmic properties and prevent the appearance of the no-reflow phenomenon in animals with coronary artery occlusion and reperfusion. Diabetes mellitus and a cholesterol-enriched diet abolish the cardioprotective effect of KCOs. Nicorandil, a KCO, attenuates major adverse cardiovascular event and the no-reflow phenomenon, reduces infarct size, and decreases the incidence of ventricular arrhythmias in patients with acute myocardial infarction.
CONCLUSION
The cardioprotective effect of KCOs is mediated by the opening of mitochondrial K (mitoK ) and sarcolemmal K (sarcK ) channels, triggered free radicals' production, and kinase activation.
Topics: Humans; Animals; No-Reflow Phenomenon; Percutaneous Coronary Intervention; Myocardial Reperfusion Injury; Apoptosis; Reperfusion; Adenosine Triphosphate; KATP Channels
PubMed: 37218378
DOI: 10.1111/fcp.12924