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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 -
European Journal of Pharmacology Oct 2023Ischemia-induced myocardial infarction is regarded as one of the major killers of humans worldwide. Kinsenoside (KD), a primary active ingredient derived from...
Ischemia-induced myocardial infarction is regarded as one of the major killers of humans worldwide. Kinsenoside (KD), a primary active ingredient derived from Anoectochilus roxburghii, shows antioxidant and vascular protective properties. Myocardial ischemia/reperfusion (I/R) injury is associated with oxidative damage and could be regulated by KD. However, its targets and the exact mechanism by which it operates remains unclear. The aim of this study was to investigate the role of KD in myocardial I/R injury and to define the mechanism by which it works. We established both myocardial I/R model in vivo and hypoxia/reoxygenation (H/R) cardiomyocyte model in vitro in this study. KD can attenuate I/R-induced myocardial injury in vivo and inhibit H/R-induced injury in vitro in a dose-dependent manner. KD increased mitochondrial membrane potential, SOD activity, and GSH activity in cardiomyocytes, whereas MDA accumulation, iron accumulation, and Mito-ROS production were decreased. We intersected differentially expressed genes (DEGs) from RNA-seq results with ferroptosis-related genes, and found KD significantly downregulated COX2 expression and upregulated GPX4 expression. These findings were further confirmed by Western blot analysis. Additionally, KD increased AKT phosphorylation and Nrf2 translocation into the nucleus, as well as HO-1 expression. When Akt or Nrf2 were inhibited in the KD group, the anti-ferroptosis properties of KD were nullified. Thus, Kinsenoside may exert anti-ferroptosis effect in myocardial I/R injury by decreasing mitochondrial dysfunction and increasing anti-oxidation through the Akt/Nrf2/HO-1 signaling pathway, suggesting it could be used as a potential therapeutic agent for myocardial reperfusion injury.
Topics: Humans; Myocardial Reperfusion Injury; Proto-Oncogene Proteins c-akt; NF-E2-Related Factor 2; Oxidative Stress; Coronary Artery Disease; Myocardial Infarction
PubMed: 37572943
DOI: 10.1016/j.ejphar.2023.175985 -
Anesthesia and Analgesia Aug 2023Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can...
BACKGROUND
Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood.
METHODS
In vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 μg/kg DEX was performed 20 minutes before ligation. Moreover, the α2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment.
RESULTS
In the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 ± 0.183; P < .0001), downregulated the inflammatory response ( P ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis ( P = .0074), and promoted the phosphorylation of STAT3 (4.94 ± 0.690 vs 6.68 ± 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 μM DEX pretreatment improved cell viability ( P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P ≤ .0040), decreased cell apoptosis ( P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 ± 0.0224 vs 0.297 ± 0.0937; P < .0001) and Ser727 (0.586 ± 0.177 vs 0.886 ± 0.0546; P = .0157), which could be abolished by Stattic.
CONCLUSIONS
DEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the α2-adrenoreceptor in vivo and in vitro.
Topics: Animals; Mice; Rats; Apoptosis; Creatine Kinase, MB Form; Dexmedetomidine; Disease Models, Animal; Hypoxia; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Reperfusion Injury; Signal Transduction; Receptors, Adrenergic, alpha
PubMed: 37145970
DOI: 10.1213/ANE.0000000000006487 -
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 -
Thrombosis Research Sep 2023Myocardial ischemia-reperfusion injury (MIRI), the joint result of ischemic injury and reperfusion injury, is associated with poor outcomes in patients with acute... (Review)
Review
Myocardial ischemia-reperfusion injury (MIRI), the joint result of ischemic injury and reperfusion injury, is associated with poor outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Accumulating evidence demonstrates that activated platelets directly contribute to the pathogenesis of MIRI through participating in the formation of microthrombi, interaction with leukocytes, secretion of active substances, constriction of microvasculature, and activation of spinal afferent nerves. The molecular mechanisms underlying the above detrimental effects of activated platelets include the homotypic and heterotypic interactions through surface receptors, transduction of intracellular signals, and secretion of active substances. Revealing the roles of platelet activation in MIRI and the associated mechanisms would provide potential targets/strategies for the clinical evaluation and treatment of MIRI. Further studies are needed to characterize the temporal (ischemia phase vs. reperfusion phase) and spatial (systemic vs. local) distributions of platelet activation in MIRI by multi-omics strategies. To improve the likelihood of translating novel cardioprotective interventions into clinical practice, basic researches maximally replicating the complexity of clinical scenarios would be necessary.
Topics: Humans; Myocardial Reperfusion Injury; Blood Platelets; Myocardial Infarction; Platelet Activation; Leukocytes
PubMed: 37437517
DOI: 10.1016/j.thromres.2023.06.022 -
Circulation Research Mar 2024The impact of circadian rhythms on cardiovascular function and disease development is well established, with numerous studies in genetically modified animals emphasizing... (Review)
Review
The impact of circadian rhythms on cardiovascular function and disease development is well established, with numerous studies in genetically modified animals emphasizing the circadian molecular clock's significance in the pathogenesis and pathophysiology of myocardial ischemia and heart failure progression. However, translational preclinical studies targeting the heart's circadian biology are just now emerging and are leading to the development of a novel field of medicine termed circadian medicine. In this review, we explore circadian molecular mechanisms and novel therapies, including (1) intense light, (2) small molecules modulating the circadian mechanism, and (3) chronotherapies such as cardiovascular drugs and meal timings. These promise significant clinical translation in circadian medicine for cardiovascular disease. (4) Additionally, we address the differential functioning of the circadian mechanism in males versus females, emphasizing the consideration of biological sex, gender, and aging in circadian therapies for cardiovascular disease.
Topics: Male; Animals; Myocardial Reperfusion Injury; Circadian Rhythm; Chronotherapy; Heart Failure; Myocardial Ischemia; Circadian Clocks
PubMed: 38484024
DOI: 10.1161/CIRCRESAHA.123.323522 -
Basic Research in Cardiology Jul 2023During myocardial ischemia and reperfusion (IR) injury matrix metalloproteinase-2 (MMP-2) is rapidly activated in response to oxidative stress. MMP-2 is a...
During myocardial ischemia and reperfusion (IR) injury matrix metalloproteinase-2 (MMP-2) is rapidly activated in response to oxidative stress. MMP-2 is a multifunctional protease that cleaves both extracellular and intracellular proteins. Oxidative stress also impairs mitochondrial function which is regulated by different proteins, including mitofusin-2 (Mfn-2), which is lost in IR injury. Oxidative stress and mitochondrial dysfunction trigger the NLRP3 inflammasome and the innate immune response which invokes the de novo expression of an N-terminal truncated isoform of MMP-2 (NTT-MMP-2) at or near mitochondria. We hypothesized that MMP-2 proteolyzes Mfn-2 during myocardial IR injury, impairing mitochondrial function and enhancing the inflammasome response. Isolated hearts from mice subjected to IR injury (30 min ischemia/40 min reperfusion) showed a significant reduction in left ventricular developed pressure (LVDP) compared to aerobically perfused hearts. IR injury increased MMP-2 activity as observed by gelatin zymography and increased degradation of troponin I, an intracellular MMP-2 target. MMP-2 preferring inhibitors, ARP-100 or ONO-4817, improved post-ischemic recovery of LVDP compared to vehicle perfused IR hearts. In muscle fibers isolated from IR hearts the rates of mitochondrial oxygen consumption and ATP production were impaired compared to those from aerobic hearts, whereas ARP-100 or ONO-4817 attenuated these reductions. IR hearts showed higher levels of NLRP3, cleaved caspase-1 and interleukin-1β in the cytosolic fraction, while the mitochondria-enriched fraction showed reduced levels of Mfn-2, compared to aerobic hearts. ARP-100 or ONO-4817 attenuated these changes. Co-immunoprecipitation showed that MMP-2 is associated with Mfn-2 in aerobic and IR hearts. ARP-100 or ONO-4817 also reduced infarct size and cell death in hearts subjected to 45 min ischemia/120 min reperfusion. Following myocardial IR injury, impaired contractile function and mitochondrial respiration and elevated inflammasome response could be attributed, at least in part, to MMP-2 activation, which targets and cleaves mitochondrial Mfn-2. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in IR injury in part by preserving Mfn-2 and suppressing inflammation.
Topics: Animals; Mice; Inflammasomes; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mitochondria; Myocardial Reperfusion Injury; Myocardium; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 37495895
DOI: 10.1007/s00395-023-00999-y -
Journal of Nanobiotechnology Aug 2023Myocardial infarction (MI) is a cardiovascular emergency and the leading cause of death worldwide. Inflammatory and immune responses are initiated immediately after MI,... (Review)
Review
Myocardial infarction (MI) is a cardiovascular emergency and the leading cause of death worldwide. Inflammatory and immune responses are initiated immediately after MI, leading to myocardial death, scarring, and ventricular remodeling. Current therapeutic approaches emphasize early restoration of ischemic myocardial reperfusion, but there is no effective treatment for the pathological changes of infarction. Biomedical materials development has brought new hope for MI diagnosis and treatment. Biomedical materials, such as cardiac patches, hydrogels, nano biomaterials, and artificial blood vessels, have played an irreplaceable role in MI diagnosis and treatment. They improve the accuracy and efficacy of MI diagnosis and offer further possibilities for reducing inflammation, immunomodulation, inhibiting fibrosis, and cardiac regeneration. This review focuses on the advances in biomedical materials applications in MI diagnosis and treatment. The current studies are outlined in terms of mechanisms of action and effects. It is addressed how biomedical materials application can lessen myocardial damage, encourage angiogenesis, and enhance heart function. Their clinical transformation value and application prospect are discussed.
Topics: Humans; Myocardial Infarction; Heart; Myocardium; Biocompatible Materials; Hydrogels
PubMed: 37626396
DOI: 10.1186/s12951-023-02063-2 -
International Journal of Nanomedicine 2024Acute inflammatory storm is a major cause of myocardial ischemia/reperfusion (I/R) injury, with no effective treatment currently available. The excessive aggregation of...
INTRODUCTION
Acute inflammatory storm is a major cause of myocardial ischemia/reperfusion (I/R) injury, with no effective treatment currently available. The excessive aggregation of neutrophils is correlated with an unfavorable prognosis in acute myocardial infarction (AMI) patients. Exosomes derived from mesenchymal stromal cells (MSC-Exo) have certain immunomodulatory potential and might be a therapeutic application. Therefore, we investigated the protective role of MSC-Exo in modulating neutrophil infiltration and formation of neutrophil extracellular traps (NETs) following myocardial I/R injury.
METHODS
Exosomes were isolated from the supernatant of MSCs using a gradient centrifugation method. We used flow cytometry, histochemistry, and immunofluorescence to detect the changes of neutrophils post-intravenous MSC-Exo injection. Additionally, cardiac magnetic resonance (CMR) and thioflavin S experiments were applied to detect microvascular obstruction (MVO). The NLR family pyrin domain containing 3 (NLRP3) inflammasome was examined for mechanism exploration. Primary neutrophils were extracted for in vitro experiment. Antibody of Ly6G was given to depleting the neutrophils in mice for verification the effect of MSC-Exo. Finally, we analyzed the MiRNA sequence of MSC-Exo and verified it in vitro.
RESULTS
MSC-Exo administration reduced neutrophil infiltration and NETs formation after myocardial I/R. MSC-Exo treatment also could attenuate the activation of NLRP3 inflammasome both in vivo and in vitro. At the same time, the infarction size and MVO following I/R injury were reduced by MSC-Exo. Moreover, systemic depletion of neutrophils partly negated the therapeutic effects of MSC-Exo. Up-regulation of miR-199 in neutrophils has been shown to decrease the expression of NETs formation after stimulation.
DISCUSSION
Our results demonstrated that MSC-Exo mitigated myocardial I/R injury in mice by modulating neutrophil infiltration and NETs formation. This study provides novel insights into the potential therapeutic application of MSC-Exo for myocardial ischemia/reperfusion injury.
Topics: Humans; Mice; Animals; Myocardial Reperfusion Injury; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Exosomes; Extracellular Traps; Neutrophil Infiltration; MicroRNAs; Reperfusion Injury
PubMed: 38476275
DOI: 10.2147/IJN.S436925 -
Phytomedicine : International Journal... Jul 2024Cardiovascular disease is the main cause of death and disability, with myocardial ischemia being the predominant type that poses a significant threat to humans.... (Review)
Review
BACKGROUND
Cardiovascular disease is the main cause of death and disability, with myocardial ischemia being the predominant type that poses a significant threat to humans. Reperfusion, an essential therapeutic approach, promptly reinstates blood circulation to the ischemic myocardium and stands as the most efficacious clinical method for myocardial preservation. Nevertheless, the restoration of blood flow associated with this process can potentially induce myocardial ischemia-reperfusion injury (MIRI), thereby diminishing the effectiveness of reperfusion and impacting patient prognosis. Therefore, it is of great significance to prevent and treat MIRI.
PURPOSE
MIRI is an important factor affecting the prognosis of patients, and there is no specific in-clinic treatment plan. In this review, we have endeavored to summarize its pathological mechanisms and therapeutic drugs to provide more powerful evidence for clinical application.
METHODS
A comprehensive literature review was conducted using PubMed, Web of Science, Embase, Medline and Google Scholar with a core focus on the pathological mechanisms and potential therapeutic drugs of MIRI.
RESULTS
Accumulated evidence revealed that oxidative stress, calcium overload, mitochondrial dysfunction, energy metabolism disorder, ferroptosis, inflammatory reaction, endoplasmic reticulum stress, pyroptosis and autophagy regulation have been shown to participate in the process, and that the occurrence and development of MIRI are related to plenty of signaling pathways. Currently, a range of chemical drugs, natural products, and traditional Chinese medicine (TCM) preparations have demonstrated the ability to mitigate MIRI by targeting various mechanisms.
CONCLUSIONS
At present, most of the research focuses on animal and cell experiments, and the regulatory mechanisms of each signaling pathway are still unclear. The translation of experimental findings into clinical practice remains incomplete, necessitating further exploration through large-scale, multi-center randomized controlled trials. Given the absence of a specific drug for MIRI, the identification of therapeutic agents to reduce myocardial ischemia is of utmost significance. For the future, it is imperative to enhance our understanding of the pathological mechanism underlying MIRI, continuously investigate and develop novel pharmaceutical agents, expedite the clinical translation of these drugs, and foster innovative approaches that integrate TCM with Western medicine. These efforts will facilitate the emergence of fresh perspectives for the clinical management of MIRI.
Topics: Humans; Myocardial Reperfusion Injury; Animals; Oxidative Stress; Endoplasmic Reticulum Stress; Autophagy; Signal Transduction; Ferroptosis; Pyroptosis
PubMed: 38653154
DOI: 10.1016/j.phymed.2024.155649