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IUBMB Life Jan 2021Myocardial ischemia/reperfusion (I/R) injury greatly contributes to myocardial tissue damage in patients with coronary disease, which eventually leads to heart failure....
Myocardial ischemia/reperfusion (I/R) injury greatly contributes to myocardial tissue damage in patients with coronary disease, which eventually leads to heart failure. Long noncoding RNAs (lncRNAs) have an emerging role in the process of myocardial I/R injury. Our previous work revealed the protective role of miR-374a-5p against myocardial I/R injury. In this study, we explored the role of lncRNA TTTY15 and its potential interaction mechanisms with miR-374a-5p in myocardial I/R injury. The expression of TTTY15 was increased both in vitro and in vivo after myocardial I/R injury models according to quantitative real-time polymerase chain reaction. Various assays were conducted to evaluate the regulatory relationship among TTTY15, miR-374a-5p, FOXO1, and autophagy in H9c2 and HL-1 cells. The results showed that TTTY15 suppresses autophagy and myocardial I/R injury by targeting miR-374a-5p. We found that TTTY15 regulates miR-374a-5p, thus affecting FOXO1 expression and autophagy in myocytes during I/R. Furthermore, in an in vivo mouse model of myocardial I/R injury, suppression of TTTY15 successfully alleviated myocardial I/R injury. Our results reveal a novel feedback mechanism in which TTTY15 regulates miRNA processing and a potential target in myocardial I/R injury. TTTY15 is a promising therapeutic target for treating myocardial I/R injury.
Topics: Animals; Apoptosis; Autophagy; Cell Hypoxia; Forkhead Box Protein O1; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Myocardial Reperfusion Injury; RNA, Long Noncoding; Signal Transduction
PubMed: 33296140
DOI: 10.1002/iub.2428 -
Cells Sep 2021Myocardial ischemia-reperfusion (I/R) injury significantly alters heart function following infarct and increases the risk of heart failure. Many studies have sought to... (Review)
Review
Myocardial ischemia-reperfusion (I/R) injury significantly alters heart function following infarct and increases the risk of heart failure. Many studies have sought to preserve irreplaceable myocardium, termed cardioprotection, but few, if any, treatments have yielded a substantial reduction in clinical I/R injury. More research is needed to fully understand the molecular pathways that govern cardioprotection. Redox mechanisms, specifically cysteine oxidations, are acute and key regulators of molecular signaling cascades mediated by kinases. Here, we review the role of reactive oxygen species in modifying cysteine residues and how these modifications affect kinase function to impact cardioprotection. This exciting area of research may provide novel insight into mechanisms and likely lead to new treatments for I/R injury.
Topics: Animals; Cysteine; Humans; Myocardial Reperfusion Injury; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 34572037
DOI: 10.3390/cells10092388 -
International Journal of Cardiology.... Jun 2019Suboptimal myocardial perfusion in primary PCI is associated with increased infarct size, left ventricular (LV) dysfunction and higher mortality rates as compared as...
BACKGROUND
Suboptimal myocardial perfusion in primary PCI is associated with increased infarct size, left ventricular (LV) dysfunction and higher mortality rates as compared as those with optimal myocardial perfusion. We identified clinical and procedural predictors of suboptimal myocardial reperfusion as judged by myocardial plush grade (MBG) in primary PCI.
METHODS AND RESULTS
100 patients with acute STEMI who underwent primary PCI were prospectively subjected to clinical, ECG, laboratory and angiographic evaluation. Patients were classified into: Optimal myocardial reperfusion group: (n=73) who had final MBG=3. Suboptimal myocardial reperfusion group: (n=27) who had persistent final MBG ≤ 2. Suboptimal myocardial reperfusion group had statistically significant little history of angina prior to MI 5 (18.5%) vs 44 (60.3%), little current aspirin intake 6(22%) vs 38 (52% ), increased blood sugar on admission (240 ± 101 mg/dl vs 171 ± 72 mg/dl), increased total leucocytic count on admission (12.1 ± 3.6 vs 10.2 ± 3.3) 103/mm3, longer reperfusion time (6.1 ± 2.8 vs 4.3 ± 2.1 h ), higher thrombus burden 12 (44.4 % ) vs 13 (17.8 %), higher predilatation pressure (16 ± 2.3 vs 14 ± 1.8 ATM), repeated balloon inflation during predilatation 24 (92.3 % ) vs 46 (69.7%) as compared optimal myocardial reperfusion group, (P < 0.05 for all).
CONCLUSION
Longer reperfusion time, repeated balloon inflations, high predilatation pressure> 15 ATM , high thrombus burden, neither history of angina nor aspirin intake prior to AMI, high total leucocytic count > 10103/mm3 and high blood glucose level > 160mg/dl were predictors for persistent suboptimal myocardial reperfusion in primary PCI.
PubMed: 31032395
DOI: 10.1016/j.ijcha.2019.100357 -
Genetics and Molecular Research : GMR Dec 2015Multiple studies have shown microRNAs to play an important role in disease occurrence and development. The role of miRNAs in ischemia-reperfusion injury, however,...
Multiple studies have shown microRNAs to play an important role in disease occurrence and development. The role of miRNAs in ischemia-reperfusion injury, however, requires further investigation and the aim of this study was therefore to assess miR-126 expression in myocardial ischemia reperfusion and the effects of miR-126 on myocardial ischemia-reperfusion injury. An in vitro model of ischemia-reperfusion injury was established using rat myocardial H9c2 cells and miR-126 expression in these cells was assessed by real-time PCR. The miR-126 mimic and inhibitor were transfected into H9c2 cells before the injury was induced. Flow cytometry and western blotting were used to assess myocardial cell apoptosis. The triphenyltetrazolium chloride method was used to assess the infarction area and a TUNEL assay was used to analyze myocardial cell apoptosis. The results of the western blot analyses indicate that the miR-126 mimic and inhibitor increase and decrease caspase 3 degradation in myocardial cells, respectively. The in vivo experiments, moreover, revealed that the miR-126 mimic and inhibitor increase and reduce the myocardial infarction area, respectively. The TUNEL assay results showed increases and decreases in apoptotic myocardial cell numbers after infusion with the miR-126 mimic or inhibitor, respectively. These findings indicate that miR-126 is down-regulated in myocardial ischemia-reperfusion injury and that the inhibition of miR-126 may protect against myocardial cell apoptosis caused by ischemia-reperfusion.
Topics: Animals; Apoptosis; Caspase 3; Cell Hypoxia; Cell Line; Female; Gene Expression; MicroRNAs; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Wistar
PubMed: 26782549
DOI: 10.4238/2015.December.29.6 -
Cardiovascular Research May 2022Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the...
AIMS
Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.
METHODS AND RESULTS
We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis.
CONCLUSION
Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.
Topics: Cathepsins; Humans; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Percutaneous Coronary Intervention; Reperfusion; ST Elevation Myocardial Infarction; Treatment Outcome
PubMed: 34132807
DOI: 10.1093/cvr/cvab204 -
Circulation Journal : Official Journal... Jan 2017Tissue salvage of severely ischemic myocardium requires timely reperfusion by thrombolysis, angioplasty, or bypass. However, recovery of left ventricular function is... (Review)
Review
Tissue salvage of severely ischemic myocardium requires timely reperfusion by thrombolysis, angioplasty, or bypass. However, recovery of left ventricular function is rare. It may be absent or, even worse, reperfusion can induce further damage. Laboratory studies have shown convincingly that reperfusion can increase injury over and above that attributable to the pre-existing ischemia, precipitating arrhythmias, suppressing the recovery of contractile function ("stunning") and possibly even causing cell death in potentially salvable ischemic tissue. The mechanisms of reperfusion injury have been widely studied and, in the laboratory, it can be attenuated or prevented. Disappointingly, this is not the case in the clinic, particularly after thrombolysis or primary angioplasty. In contrast, excellent results have been achieved by surgeons by means of cardioplegia and hypothermia. For the interventionist, the issue is more complex as, contrary to cardiac surgery where the cardioplegia can be applied before ischemia and the heart can be stopped, during an angioplasty the heart still has to beat to support the circulation. We analyze in detail all these issues.
Topics: Animals; Humans; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Time Factors; Ventricular Function, Left
PubMed: 27941300
DOI: 10.1253/circj.CJ-16-1124 -
Nature Reviews. Cardiology Nov 2017Early coronary artery reperfusion improves outcomes for patients with ST-segment elevation myocardial infarction (STEMI), but morbidity and mortality after STEMI remain... (Review)
Review
Early coronary artery reperfusion improves outcomes for patients with ST-segment elevation myocardial infarction (STEMI), but morbidity and mortality after STEMI remain unacceptably high. The primary deficits seen in these patients include inadequate pump function, owing to rapid infarction of muscle in the first few hours of treatment, and adverse remodelling of the heart in the months that follow. Given that attempts to further reduce myocardial infarct size beyond early reperfusion in clinical trials have so far been disappointing, effective therapies are still needed to protect the reperfused myocardium. In this Review, we discuss several approaches to preserving the reperfused heart, such as therapies that target the mechanisms involved in mitochondrial bioenergetics, pyroptosis, and autophagy, as well as treatments that harness the cardioprotective properties of inhaled anaesthetic agents. We also discuss potential therapies focused on correcting the no-reflow phenomenon and its effect on healing and adverse left ventricular remodelling.
Topics: Coronary Circulation; Humans; Myocardial Reperfusion; No-Reflow Phenomenon; Postoperative Period; ST Elevation Myocardial Infarction; Ventricular Remodeling
PubMed: 28748958
DOI: 10.1038/nrcardio.2017.102 -
Kardiologia Polska 2024Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation... (Review)
Review
Patients with transient ST-segment elevation myocardial infarction or spontaneous reperfusion, which occurs in approximately 20% of patients with ST-segment elevation myocardial infarction (STEMI), have smaller infarcts and more favorable clinical outcomes than patients without spontaneous reperfusion. Understanding the mechanisms underlying spontaneous reperfusion is therefore important since this may identify possible novel therapeutic targets to improve outcomes in patients with STEMI. In this review, we discuss some of the possible determinants of spontaneous reperfusion including pro-thrombotic profile, endogenous fibrinolytic status, lipoprotein(a) (Lp[a]), inflammatory markers, and neutrophil extracellular traps (NETs). Effective (rapid) endogenous fibrinolysis, as assessed in whole blood in vitro, using a point-of-care technique assessment of global thrombotic status, has been strongly linked to spontaneous reperfusion. Lp(a), which has a high degree of homology to plasminogen, may impair fibrinolysis through competitive inhibition of tissue plasminogen activator-mediated plasminogen activation as well as tissue plasminogen activator-mediated clot lysis and contribute to pathogenic clot properties by decreasing fibrin clot permeation. NETs appear to negatively modulate clot lysis by increasing thrombin fiber diameter and inhibiting plasmin-driven lysis of plasma clots. There are limited data that oral anticoagulation may modulate endogenous fibrinolysis but antiplatelet agents currently appear to have no impact. Phase III trials involving subcutaneous P2Y12 or glycoprotein IIb/IIIa inhibitors, oral factor XIa inhibitors, interleukin-6 inhibitors, and apolipoprotein(a) antisense oligonucleotides in patients with cardiovascular disease are ongoing. Future studies will be needed to determine the impact of these novel antithrombotic, anti-inflammatory, and lipid-lowering therapies on endogenous fibrinolysis and spontaneous reperfusion.
Topics: Humans; ST Elevation Myocardial Infarction; Fibrinolysis; Extracellular Traps; Myocardial Reperfusion; Lipoprotein(a)
PubMed: 38493469
DOI: 10.33963/v.phj.99737 -
British Journal of Pharmacology Apr 2015The protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago... (Review)
Review
The protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago commanding intense interest as an approach for modifying reperfusion injury which contributes to infarct size in acute myocardial infarction. Elucidation of the major mechanisms of postconditioning has identified potential pharmacological targets for limitation of reperfusion injury. These include ligands for membrane-associated receptors, activators of phosphokinase survival signalling pathways and inhibitors of the mitochondrial permeability transition pore. In experimental models, numerous agents that target these mechanisms have shown promise as postconditioning mimetics. Nevertheless, clinical studies of ischaemic postconditioning and pharmacological postconditioning mimetics are equivocal. The majority of experimental research is conducted in animal models which do not fully portray the complexity of risk factors and comorbidities with which patients present and which we now know modify the signalling pathways recruited in postconditioning. Cohort size and power, patient selection, and deficiencies in clinical infarct size estimation may all represent major obstacles to assessing the therapeutic efficacy of postconditioning. Furthermore, chronic treatment of these patients with drugs like ACE inhibitors, statins and nitrates may modify signalling, inhibiting the protective effect of postconditioning mimetics, or conversely induce a maximally protected state wherein no further benefit can be demonstrated. Arguably, successful translation of postconditioning cannot occur until all of these issues are addressed, that is, experimental investigation requires more complex models that better reflect the clinical setting, while clinical investigation requires bigger trials with appropriate patient selection and standardization of clinical infarct size measurements.
Topics: Animals; Humans; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Signal Transduction
PubMed: 25303373
DOI: 10.1111/bph.12976 -
Biomedicine & Pharmacotherapy =... Nov 2022Insufficiency in coronary blood supply results in myocardial ischemia and consequently, various clinical syndromes and irreversible injuries. Myocardial damage occurs as... (Review)
Review
Insufficiency in coronary blood supply results in myocardial ischemia and consequently, various clinical syndromes and irreversible injuries. Myocardial damage occurs as a result of two processes during acute myocardial infarction (MI): ischemia and subsequent reperfusion. According to the available evidence, oxidative stress, excessive inflammation reaction, reactive oxygen species (ROS) generation, and apoptosis are crucial players in the pathogenesis of myocardial ischemia/reperfusion (IR) injury. There is emerging evidence that Janus tyrosine kinase 2 (JAK2) signal transducer and activator of the transcription 3 (STAT3) pathway offers cardioprotection against myocardial IR injury. This article reviews therapeutics that exert cardioprotective effects against myocardial IR injury through induction of JAK2/STAT3 pathway.
Topics: Humans; Myocardial Reperfusion Injury; Reactive Oxygen Species; TYK2 Kinase; Janus Kinase 2; STAT3 Transcription Factor; Myocardial Ischemia; Myocardial Infarction; Apoptosis; Reperfusion
PubMed: 36162372
DOI: 10.1016/j.biopha.2022.113751