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Biochemical and Biophysical Research... Jul 2023The translocation of Drp1 from the cytosol to mitochondria leads to Drp1 activation and mitochondrial fission in myocardial ischemia/reperfusion (MI/R). However, the...
The translocation of Drp1 from the cytosol to mitochondria leads to Drp1 activation and mitochondrial fission in myocardial ischemia/reperfusion (MI/R). However, the molecular mechanism underlying mitochondrial Drp1 translocation remains poorly understood. Mitochondrial Drp1 recruitment relies on 4 binding partners including MiD49, MiD51, Mff and Fis1. This study was to elucidate which one facilitate mitochondrial Drp1 translocation and its role in MI/R injury. MI/R was induced by ligating the left anterior descending coronary artery for 30 min and subsequent reperfusion for 3 h. Primary neonatal cardiomyocytes were subjected to hypoxia for 2 h and reoxygenation for 4 h. SiRNA or Adeno-associated virus (AAV) expressing shRNA was used to knock down the key binding partner in vitro or in vivo respectively. The expression of MiD51 rather than other binding partners (MiD49, Mff or Fis1) was increased after MI/R. MiD51 knockdown inhibited hypoxia/reoxygenation (H/R) or ischemia/reperfusion (I/R)-induced mitochondrial Drp1 translocation. SiRNA-induced knockdown of MiD51 suppressed mitochondrial oxidative stress, improved mitochondrial function and alleviate cellular injury in H/R cardiomyocytes. AAV-mediated knockdown of MiD51 reduced myocardial injury and improved cardiac function in the I/R hearts, while mitochondrial Drp1 translocation and cardiac function were not affected by MiD51 knockdown in the hearts without I/R. MiD51 is identified as the binding partner that promotes mitochondrial Drp1 translocation and contributes to MI/R injury. Inhibition of MiD51 may be a potential therapeutic target to alleviate MI/R injury.
Topics: Humans; Infant, Newborn; Apoptosis; Dynamins; Ischemia; Mitochondria; Mitochondrial Dynamics; Myocardial Ischemia; Reperfusion; RNA, Small Interfering; Up-Regulation
PubMed: 37149986
DOI: 10.1016/j.bbrc.2023.05.013 -
JAMA Mar 2024
Topics: Humans; Reperfusion; Stroke; Glucocorticoids
PubMed: 38329442
DOI: 10.1001/jama.2024.0526 -
European Journal of Pharmacology May 2024Ischemic heart disease, a prevalent cardiovascular disease with global significance, is associated with substantial morbidity. Timely and successful reperfusion is... (Review)
Review
Ischemic heart disease, a prevalent cardiovascular disease with global significance, is associated with substantial morbidity. Timely and successful reperfusion is crucial for reducing infarct size and enhancing clinical outcomes. However, reperfusion may induce additional myocardium injury, manifesting as myocardial ischemia/reperfusion (MI/R) injury. Pyroptosis is a regulated cell death pathway, the signaling pathway of which is activated during MI/R injury. In this process, the inflammasomes are triggered, initiating the cleavage of gasdermin proteins and pro-interleukins, which results in the formation of membrane pores and the maturation and secretion of inflammatory cytokines. Numerous preclinical evidence underscores the pivotal role of pyroptosis in MI/R injury. Inhibiting pyroptosis is cardioprotective against MI/R injury. Although certain agents exhibiting promise in preclinical studies for attenuating MI/R injury through inhibiting pyroptosis have been identified, the suitability of these compounds for clinical trials remains untested. This review comprehensively summarizes the recent developments in this field, with a specific emphasis on the impact of pyroptosis on MI/R injury. Deciphering these findings not only sheds light on new disease mechanisms but also paves the way for innovative treatments. And then the exploration of the latest advances in compounds that inhibit pyroptosis in MI/R is discussed, which aims to provide insights into potential therapeutic strategies and identify avenues for future research in the pursuit of effective clinical interventions.
Topics: Humans; Myocardial Reperfusion Injury; Pyroptosis; Inflammasomes; Ischemia; Reperfusion; NLR Family, Pyrin Domain-Containing 3 Protein; Reperfusion Injury
PubMed: 38461908
DOI: 10.1016/j.ejphar.2024.176464 -
Med (New York, N.Y.) Jan 2024Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion is the pathophysiological substrate of... (Review)
Review
Ischemic heart disease is the greatest health burden and most frequent cause of death worldwide. Myocardial ischemia/reperfusion is the pathophysiological substrate of ischemic heart disease. Improvements in prevention and treatment of ischemic heart disease have reduced mortality in developed countries over the last decades, but further progress is now stagnant, and morbidity and mortality from ischemic heart disease in developing countries are increasing. Significant problems remain to be resolved and require a better pathophysiological understanding. The present review attempts to briefly summarize the state of the art in myocardial ischemia/reperfusion research, with a view on both its coronary vascular and myocardial aspects, and to define the cutting edges where further mechanistic knowledge is needed to facilitate translation to clinical practice.
Topics: Humans; Myocardial Reperfusion Injury; Myocardial Ischemia; Myocardial Reperfusion; Myocardium
PubMed: 38218174
DOI: 10.1016/j.medj.2023.12.007 -
Cells Jul 2023Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric... (Review)
Review
Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted.
Topics: Humans; Soluble Guanylyl Cyclase; Hypertension, Pulmonary; Signal Transduction; Ischemia; Reperfusion
PubMed: 37508567
DOI: 10.3390/cells12141903 -
GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion.Journal of Molecular Medicine (Berlin,... Nov 2023Reperfusion after acute myocardial infarction further exaggerates cardiac injury and adverse remodeling. Irrespective of cardiac cell types, loss of specifically the α...
Reperfusion after acute myocardial infarction further exaggerates cardiac injury and adverse remodeling. Irrespective of cardiac cell types, loss of specifically the α isoform of the protein kinase GSK-3 is protective in chronic cardiac diseases. However, the role of GSK-3α in clinically relevant ischemia/reperfusion (I/R)-induced cardiac injury is unknown. Here, we challenged cardiomyocyte-specific conditional GSK-3α knockout (cKO) and littermate control mice with I/R injury and investigated the underlying molecular mechanism using an in vitro GSK-3α gain-of-function model in AC16 cardiomyocytes post-hypoxia/reoxygenation (H/R). Analysis revealed a significantly lower percentage of infarct area in the cKO vs. control hearts post-I/R. Consistent with in vivo findings, GSK-3α overexpression promoted AC16 cardiomyocyte death post-H/R which was accompanied by an induction of reactive oxygen species (ROS) generation. Consistently, GSK-3α gain-of-function caused mitochondrial dysfunction by significantly suppressing mitochondrial membrane potential. Transcriptomic analysis of GSK-3α overexpressing cardiomyocytes challenged with hypoxia or H/R revealed that NOD-like receptor (NLR), TNF, NF-κB, IL-17, and mitogen-activated protein kinase (MAPK) signaling pathways were among the most upregulated pathways. Glutathione and fatty acid metabolism were among the top downregulated pathways post-H/R. Together, these observations suggest that loss of cardiomyocyte-GSK-3α attenuates cardiac injury post-I/R potentially through limiting the myocardial inflammation, mitochondrial dysfunction, and metabolic derangement. Therefore, selective inhibition of GSK-3α may provide beneficial effects in I/R-induced cardiac injury and remodeling. KEY MESSAGES: GSK-3α promotes cardiac injury post-ischemia/reperfusion (I/R). GSK-3α regulates inflammatory and metabolic pathways post-hypoxia/reoxygenation (H/R). GSK-3α overexpression upregulates NOD-like receptor (NLR), TNF, NF-kB, IL-17, and MAPK signaling pathways in cardiomyocytes post-H/R. GSK-3α downregulates glutathione and fatty acid metabolic pathways in cardiomyocytes post-H/R.
Topics: Mice; Animals; Glycogen Synthase Kinase 3; Interleukin-17; Myocytes, Cardiac; Reperfusion Injury; Myocardial Infarction; NF-kappa B; Coronary Artery Disease; Hypoxia; Reperfusion; Inflammation; Glutathione; NLR Proteins; Fatty Acids; Apoptosis
PubMed: 37707557
DOI: 10.1007/s00109-023-02373-w -
Journal of Cerebral Blood Flow and... Jul 2023Despite progress in reperfusion therapy, functional recovery remains suboptimal in many stroke patients, with oxidative stress, inflammation, dysbiosis, and secondary...
Despite progress in reperfusion therapy, functional recovery remains suboptimal in many stroke patients, with oxidative stress, inflammation, dysbiosis, and secondary neurodegeneration constituting the major hurdles to recovery. The essential trace element selenium is emerging as a promising therapeutic agent for stroke. However, although several rodent studies have shown that selenium can protect against cell loss following cerebral ischemia, no study has yet examined whether selenium can enhance long-term functional recovery. Moreover, published studies have typically reported a single mechanism of action underlying selenium-mediated stroke recovery. However, we propose that selenium is more likely to have multifaceted actions. Here, we show that selenomethionine confers a potent neuroprotective effect in a canonical filament-induced transient middle cerebral artery occlusion (tMCAO) mouse model. Post-tMCAO selenium treatment significantly reduces the cerebral infarct volume, oxidative stress, and ferroptosis and enhances post-tMCAO motor performance in the acute phase after stroke. Moreover, analysis of the gut microbiota reveals that acute selenium treatment reverses stroke-induced gut dysbiosis. Longer-term selenium supplementation activates intrinsic neuroprotective mechanisms, prevents secondary neurodegeneration, alleviates systemic inflammation, and diminishes gut microbe-derived circulating trimethylamine N-oxide. These findings demonstrate that selenium treatment even after cerebral ischemia has long-term and multifaceted neuroprotective effects, highlighting its clinical potential.
Topics: Mice; Animals; Selenium; Neuroprotection; Dysbiosis; Brain Ischemia; Stroke; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Dietary Supplements; Reperfusion Injury
PubMed: 36756891
DOI: 10.1177/0271678X231156981 -
Neurology Apr 2024Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date.
METHODS
We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073).
RESULTS
There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group ( < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group.
DISCUSSION
In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.
Topics: Humans; Fibrinolytic Agents; Brain Ischemia; Thrombolytic Therapy; Stroke; Cerebral Hemorrhage; Ischemic Stroke; Reperfusion; Treatment Outcome; Thrombectomy
PubMed: 38457772
DOI: 10.1212/WNL.0000000000207983 -
Journal of Clinical Medicine Jul 2023Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident... (Review)
Review
Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CXCL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CXCR1. We have shown previously that the fractalkine receptor CXCR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CXCR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CXCR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.
PubMed: 37510939
DOI: 10.3390/jcm12144821 -
International Journal of Molecular... Nov 2023Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although...
Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although excitotoxicity is considered the primary mechanism of cell death during an ischemic event, antagonists of glutamatergic receptors have been unsuccessful in clinical trials with patients suffering ischemia or stroke. Our main purpose was to analyze if the transient receptor potential channel 7 (TRPM7) could contribute to retinal dysfunction in retinal pathologies associated with ischemia. By using an experimental model of acute retinal ischemia, we analyzed the changes in retinal function by electroretinography and the changes in retinal morphology by optical coherence tomography (OCT) and OCT-angiography (OCTA). Immunohistochemistry was performed to assess the pattern of TRPM7 and its expression level in the retina. Our results show that ischemia elicited a decrease in retinal responsiveness to light stimuli along with reactive gliosis and a significant increase in the expression of TRPM7 in Müller cells. TRPM7 could emerge as a new drug target to be explored in retinal pathologies associated with ischemia.
Topics: Animals; Humans; Infant, Newborn; Mice; Ischemia; Protein Serine-Threonine Kinases; Reperfusion; Retina; Retinal Diseases; Retinal Vessels; TRPM Cation Channels
PubMed: 38003256
DOI: 10.3390/ijms242216068