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Biomedicine & Pharmacotherapy =... Sep 2023The current study intended to delve into the mechanisms of dexmedetomidine (Dex) in regulating myocardial pyroptosis against myocardial ischemia/reperfusion injury...
The current study intended to delve into the mechanisms of dexmedetomidine (Dex) in regulating myocardial pyroptosis against myocardial ischemia/reperfusion injury (MIRI). The rat MIRI models were induced by ligation/release of the coronary artery in vivo and Langendorff perfusion ex vivo. Hemodynamic parameters, infarction sizes, and histopathological changes were assessed to understand the effects of Dex on MIRI. We explored the mechanisms through functional experiments on an H9c2 cell hypoxia/reoxygenation (H/R) model. Cell viability and apoptosis were evaluated using cell counting kit 8 (CCK-8) and AV/PI dual staining respectively. The expressions of miR-665 and MEF2D mRNA were detected by qRT-PCR. Western blot was employed to determine the expression levels of pyroptosis- and signaling pathway- related proteins. The interplays between miR-665 and MEF2D were validated by Dual-luciferase reporter assays. Our findings indicated that Dex preconditioning dramatically attenuated hemodynamic derangements, infarct size, and histopathological damage in rats undergoing MIRI. Dex markedly augmented cell viability, while suppressing cell apoptosis and expressions of NLRP3, cleaved-caspase-1, ASC, GSDMD, IL-1β, and IL-18 in H9c2 cells subjected to H/R injury. MiR-665 was significantly upregulated, MEF2D and Nrf2 downregulated following H/R, whereas Dex preconditioning reversed these changes. MEF2D was validated to be a target gene of miR-665. Overexpression of miR-665 decreased the expression of MEF2D and blunted the protective effects of Dex in H9c2 cells. Moreover, the functional rescue experiment further verified that Dex regulated MEF2D/Nrf2 pathway via miR-665. In conclusion, Dex mitigates MIRI through inhibiting pyroptosis via regulating miR-665/MEF2D/Nrf2 axis.
Topics: Rats; Animals; Myocardial Reperfusion Injury; Pyroptosis; Dexmedetomidine; NF-E2-Related Factor 2; Cell Line; MicroRNAs; Apoptosis; Myocytes, Cardiac; Reperfusion Injury; MEF2 Transcription Factors
PubMed: 37549462
DOI: 10.1016/j.biopha.2023.115255 -
Journal of Cardiovascular Pharmacology... Nov 2021Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous... (Review)
Review
Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.
Topics: Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Oxidative Stress
PubMed: 34534022
DOI: 10.1177/10742484211046674 -
International Journal of Molecular... Mar 2022Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as... (Review)
Review
Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia-reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.
Topics: Humans; MicroRNAs; Myocardial Infarction; Myocardial Reperfusion Injury; Nucleotides; RNA, Long Noncoding; RNA, Untranslated
PubMed: 35269870
DOI: 10.3390/ijms23052728 -
Basic Research in Cardiology Jan 2023Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis....
Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.
Topics: Rats; Male; Animals; Imatinib Mesylate; Rats, Wistar; Myocardial Infarction; Heart; Myocardium; Myocardial Reperfusion Injury; Myocardial Reperfusion
PubMed: 36639597
DOI: 10.1007/s00395-022-00974-z -
Protective Mechanism and Clinical Application of Hydrogen in Myocardial Ischemia-reperfusion Injury.Pakistan Journal of Biological Sciences... Jan 2020Cardiovascular disease accounts for one-third of all deaths, with ischemic heart disease as the main cause of death. Under pathological conditions, ischemia-reperfusion... (Review)
Review
Cardiovascular disease accounts for one-third of all deaths, with ischemic heart disease as the main cause of death. Under pathological conditions, ischemia-reperfusion injury (IRI) often occurs in tissues. Ischemic injury is mainly caused by anaerobic cell death and reperfusion which results in a wide range of inflammatory responses. These responses are able to increase tissue damage and even damage to the whole body. IRI can also aggravate the original cardiovascular disease during the treatment of cardiovascular disease. Therefore, it is particularly important to understand the mechanism of myocardial ischemia-reperfusion injury (MIRI) for clinical treatment and application. At the same time, it is necessary to find a safe, reliable and feasible method for treating MIRI to reduce the incidence of complications and mortality as well as improve the prognosis and quality of life of patients. As a selective antioxidant, hydrogen can neutralize excessive free radicals, has certain anti-apoptotic and anti-inflammatory effects and it has gradually become a focus and hotspot of preclinical and clinical research. Hydrogen has been shown to have a certain therapeutic effect on MIRI, which can provide a new therapeutic direction for the clinical treatment of myocardial ischemia-reperfusion injury. In this review, the protective mechanism and clinical application of hydrogen in myocardial ischemia-reperfusion injury is discussed.
Topics: Animals; Antioxidants; Calcium; Cardiovascular Diseases; Free Radicals; Humans; Hydrogen; Mice; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Oxidative Stress; Xanthine Dehydrogenase
PubMed: 31944068
DOI: 10.3923/pjbs.2020.103.112 -
Steroids Sep 2020Anabolic steroids (AS) are synthetic testosterone-derivatives developed by the pharmaceutical industry to mimic testosterone biological effects. So far, AS have been... (Review)
Review
Anabolic steroids (AS) are synthetic testosterone-derivatives developed by the pharmaceutical industry to mimic testosterone biological effects. So far, AS have been implicated in the treatment of pathological conditions, such as hypogonadism, anemia, and cachexia. Since their discovery, though, AS have been illicitly used by elite and recreational athletes, bodybuilders and weightlifters in order to enhance athletic and aesthetic performance. This practice is characterized by cycles of administration and withdrawal, the combination of different AS compounds, and administration of doses 50 - 1000 times higher than those recommended for therapeutic purposes. AS excess has been correlated to cardiovascular detrimental effects, including cardiac hypertrophy, arrhythmias, and hypertension. Particularly, acute myocardial infarction (AMI) has been extensively reported by clinical and post-mortem studies. Atherosclerosis, hypercoagulability state, increased thrombogenesis and vasospasm have arisen as potential causes of myocardial ischemia in AS users. Additionally, several experimental reports have demonstrated that AS can increase the susceptibility to cardiac ischemia/reperfusion injury, whereas the cardioprotection elicited by physical exercise and ischemic postconditioning is blunted. Altogether, these factors can contribute to increased AMI morbidity and mortality during AS excess, particularly when AS are combined with other compounds, such as thyroid hormones, growth hormones, insulin, and diuretics.
Topics: Animals; Atrial Remodeling; Dose-Response Relationship, Drug; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Testosterone Congeners
PubMed: 32492466
DOI: 10.1016/j.steroids.2020.108660 -
Journal of Cardiovascular Pharmacology Feb 2021Hydrogen sulfide (H2S), generally known as a new gas signal molecule after nitric oxide and carbon monoxide, has been found as an important endogenous gasotransmitter in... (Review)
Review
Hydrogen sulfide (H2S), generally known as a new gas signal molecule after nitric oxide and carbon monoxide, has been found as an important endogenous gasotransmitter in the last few decades, and it plays a significant role in the cardiovascular system both pathologically and physiologically. In recent years, there is growing evidence that H2S provides myocardial protection against myocardial ischemia-reperfusion injury (MIRI), which resulted in an ongoing focus on the possible mechanisms of action accounting for the H2S cardioprotective effect. At present, lots of mechanisms of action have been verified through in vitro and in vivo models of I/R injury, such as S-sulfhydrated modification, antiapoptosis, effects on microRNA, bidirectional effect on autophagy, antioxidant stress, or interaction with NO and CO. With advances in understanding of the molecular pathogenesis of MIRI and pharmacology studies, the design, the development, and the pharmacological characterization of H2S donor drugs have made great important progress. This review summarizes the latest research progress on the role of H2S in MIRI, systematically explains the molecular mechanism of H2S affecting MIRI, and provides a new idea for the formulation of a myocardial protection strategy in the future.
Topics: Animals; Carbon Monoxide; Cardiovascular System; Cell Death; Gasotransmitters; Humans; Hydrogen Sulfide; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Signal Transduction
PubMed: 33165141
DOI: 10.1097/FJC.0000000000000943 -
American Journal of Physiology. Heart... Jul 2021There is a lack of understanding in the cardiac remodeling field regarding the use of nonreperfused myocardial infarction (MI) and reperfused MI in animal models of MI....
There is a lack of understanding in the cardiac remodeling field regarding the use of nonreperfused myocardial infarction (MI) and reperfused MI in animal models of MI. This Perspectives summarizes the consensus of the authors regarding how to select the optimum model for your experiments and is a part of ongoing efforts to establish rigor and reproducibility in cardiac physiology research.
Topics: Animals; Disease Models, Animal; Heart; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion
PubMed: 34114891
DOI: 10.1152/ajpheart.00234.2021 -
Kardiologia Polska Oct 2019Little attention is paid to the coronary microvasculature when treating acute myocardial infarction (MI). Microvascular obstruction (MVO) contributes to... (Review)
Review
Little attention is paid to the coronary microvasculature when treating acute myocardial infarction (MI). Microvascular obstruction (MVO) contributes to ischemia-reperfusion injury, which hampers distal blood flow to the myocardium despite recanalization of the culprit epicardial vessel. One of the mechanisms behind reperfusion injury is MVO due to persistent vasoconstrictor tone during reperfusion. Arginine vasopressin (AVP) is a hormone with prominent vasoactive effects on the coronary microvessels. Its levels are elevated as part of a stress response triggered by MI, which was shown to exert vasoconstrictive effects on the coronary arteries in preclinical models, mainly in the nonepicardial vessels of the microcirculation. Circulating AVP levels are up to 100‑fold higher in MI and do not immediately decrease to baseline levels on reperfusion. This results in the so called coronary slow flow phenomenon and mediates ischemia-reperfusion injury. Recently, the C‑terminal fragment of preprovasopressin, copeptin, has emerged as a surrogate biomarker for AVP, as it is more stable in the circulation. Multiple studies have shown the predictive value of both AVP and copeptin with regards to long‑term prognoses of MI patients. We propose that both AVP and copeptin have more than just a predictive value but also play a role in the pathophysiology of adverse outcome post‑MI. Therefore, the treatment of choice for MI should not only focus on the epicardial vessel but also on targeting MVO that might pre‑exist or might directly follow reperfusion. This mandates a clinical trial with an AVP‑receptor antagonist in patients with acute MI undergoing reperfusion therapy.
Topics: Animals; Arginine Vasopressin; Humans; Myocardial Infarction; Myocardial Reperfusion
PubMed: 31553327
DOI: 10.33963/KP.14986 -
Journal of Controlled Release :... Jan 2023Myocardial ischemia-reperfusion injury (IRI) is becoming a typical cardiovascular disease with increasing worldwide incidence. It is usually induced by the restoration... (Review)
Review
Myocardial ischemia-reperfusion injury (IRI) is becoming a typical cardiovascular disease with increasing worldwide incidence. It is usually induced by the restoration of normal blood flow to the ischemic myocardium after a period of recanalization and directly leads to myocardial damage. Notably, the pathological mechanism of myocardial IRI is closely related to inflammation, oxidative stress, Ca overload, and the opening of mitochondrial permeability transition pore channels. Therefore, monitoring of these changes and imaging lesions is a key to timely clinical diagnosis. Nanomedicines have shown great value in the diagnosis and treatment of myocardial IRI, with advantages including passive/active targeting, prolonged circulation, improved bioavailability, versatile carrier selection, and synergistic integration of different imaging and therapeutic agents in single particles with the same pharmaceutics. Because theranostic nanomedicines for myocardial IRI have advanced rapidly, we conduct an updated review on this topic. The special focus is on how to rationally design the nanomedicines to achieve optimal imaging and therapy. We hope this review would stimulate the interest of researchers with different backgrounds and expedite the development of nanomedicines for myocardial IRI.
Topics: Humans; Myocardial Reperfusion Injury; Nanomedicine; Myocardium; Oxidative Stress
PubMed: 36496052
DOI: 10.1016/j.jconrel.2022.11.057