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Vascular Pharmacology Dec 2020In the last few decades extracellular vesicles (EVs), which include exosomes and microvesicles, have attracted significant interest in cardiovascular pathophysiology due... (Review)
Review
In the last few decades extracellular vesicles (EVs), which include exosomes and microvesicles, have attracted significant interest in cardiovascular pathophysiology due to their intrinsic properties. Indeed, EVs by transferring their cargo, which contains miRNA, DNA, proteins and lipids, were found effective in preventive and regenerative medicine and in protecting the heart against an array of pathological conditions, including myocardial infarction and arrhythmias. EVs can attenuate cellular senescence, inflammation and myocardial injury. Cardiovascular structures may be targeted by circulating EVs derived by extra-cardiac cells and platelets, as well by EVs locally released from all major cardiovascular cell types, including endothelial cells, cardiomyocytes, macrophages and fibroblasts. Yet, EVs of cardiovascular origin can be also transferred to distant tissues by circulation. Therefore, EVs have been proposed not only as promising diagnostic tools (early disease biomarkers), but also as therapeutics. This review focuses on the protective effects exerted by EVs, released by different cell types in the cardiovascular system. Physical exercise is considered as a natural mechanism of EV production involved in preventive medicine. Particular attention will be devoted to describe the impact of EVs in cardioprotection after ischemia/reperfusion injury.
Topics: Animals; Blood Platelets; Cardiovascular Diseases; Cardiovascular System; Cellular Microenvironment; Endothelial Cells; Exercise; Extracellular Vesicles; Humans; Mesenchymal Stem Cells; Myocardial Reperfusion Injury; Signal Transduction
PubMed: 32861822
DOI: 10.1016/j.vph.2020.106790 -
BioMed Research International 2020This project is aimed at investigating whether CircANXA2 can promote the apoptosis of myocardial cells by inhibiting miR-133 expression and thereby participate in the...
OBJECTIVE
This project is aimed at investigating whether CircANXA2 can promote the apoptosis of myocardial cells by inhibiting miR-133 expression and thereby participate in the development of myocardial ischemia-reperfusion injury. . Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of CircANXA2 in H9c2 cells after hypoxia/reoxygenation (H/R) treatment. Evaluation of myocardial injury markers in H9c2 cells was performed using commercial kits, including lactate dehydrogenase (LDH), malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidation (GSH-PX). MTT analysis and flow cytometry were used to detect myocardial cell proliferation and apoptosis, respectively. Western blot was used to detect the protein expression of apoptosis-related genes.
RESULT
qRT-PCR results showed that compared with the control, the expression of CircANXA2 was upregulated and the expression level of miR-133 was significantly decreased in H/R-treated H9c2 cells. CircANXA2 overexpression increased LDH, MDA, SOD, and GSH-PX activity in H/R-treated H9c2 cells. At the same time, CircANXA2 overexpression inhibited the proliferation of H/R-treated cells, and CircANXA2 was able to induce cardiomyocyte apoptosis. Western blot results showed that after overexpression of CircANXA2, the proapoptotic genes Bax and cytochrome C was upregulated, while the antiapoptotic gene Bcl-2 was downregulated. In H9c2 cells, upregulating miR-133 can reverse the inhibition of proliferation induced by CircANXA2 overexpression and increase apoptosis.
CONCLUSIONS
CircANXA2 promotes cardiomyocyte apoptosis in myocardial ischemia-reperfusion injury by inhibiting the expression of miR-133. CircANXA2 may be a potential target for myocardial ischemia-reperfusion injury.
Topics: Animals; Apoptosis; Cell Line; Gene Expression Regulation; MicroRNAs; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; RNA, Circular; Rats
PubMed: 32685535
DOI: 10.1155/2020/8590861 -
Therapeutic Hypothermia and Temperature... Jun 2022In acute myocardial infarction (AMI), myocardial reperfusion injury may undo part of the recovery after revascularization of the occluded coronary artery. Selective... (Observational Study)
Observational Study
Ultrastructural Characteristics of Myocardial Reperfusion Injury and Effect of Selective Intracoronary Hypothermia: An Observational Study in Isolated Beating Porcine Hearts.
In acute myocardial infarction (AMI), myocardial reperfusion injury may undo part of the recovery after revascularization of the occluded coronary artery. Selective intracoronary hypothermia is a novel method aimed at reducing myocardial reperfusion injury, but its presumed protective effects in AMI still await further elucidation. This proof-of-concept study assesses the potential protective effects of selective intracoronary hypothermia in an , isolated beating heart model of AMI. In four isolated Langendorff perfused beating pig hearts, an anterior wall myocardial infarction was created by inflating a balloon in the mid segment of the left anterior descending (LAD) artery. After one hour, two hearts were treated with selective intracoronary hypothermia followed by normal reperfusion (cooled hearts). In the other two hearts, the balloon was deflated after one hour, allowing normal reperfusion (control hearts). Biopsies for histologic and electron microscopic evaluation were taken from the myocardium at risk at different time points: before occlusion (t = BO); 5 minutes before reperfusion (t = BR); and 10 minutes after reperfusion (t = AR). Electron microscopic analysis was performed to evaluate the condition of the mitochondria. Histological analyses included evaluation of sarcomeric collapse and intramyocardial hematoma. Electron microscopic analysis revealed intact mitochondria in the hypothermia treated hearts compared to the control hearts where mitochondria were more frequently damaged. No differences in the prespecified histological parameters were observed between cooled and control hearts at t = AR. In the isolated beating porcine heart model of AMI, reperfusion was associated with additional myocardial injury beyond ischemic injury. Selective intracoronary hypothermia preserved mitochondrial integrity compared to nontreated controls.
Topics: Animals; Hypothermia; Hypothermia, Induced; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Swine
PubMed: 34847796
DOI: 10.1089/ther.2021.0025 -
Expert Opinion on Pharmacotherapy Oct 2020Achieving reperfusion immediately after acute myocardial infarction improves outcomes; despite this, patients remain at a high risk for mortality and morbidity at least... (Review)
Review
INTRODUCTION
Achieving reperfusion immediately after acute myocardial infarction improves outcomes; despite this, patients remain at a high risk for mortality and morbidity at least for the first year after the event. Ischemia-reperfusion injury (IRI) has a complex pathophysiology and plays an important role in myocardial tissue injury, repair, and remodeling.
AREAS COVERED
In this review, the authors discuss the various mechanisms and their pharmacological agents currently available for reducing myocardial ischemia-reperfusion injury (IRI). They review important original investigations and trials in various clinical databases for treatments targeting IRI.
EXPERT OPINION
Encouraging results observed in many preclinical studies failed to show similar success in attenuating myocardial IRI in large-scale clinical trials. Identification of critical risk factors for IRI and targeting them individually rather than one size fits all approach should be the major focus of future research. Various newer therapies like tocilizumab, anakinra, colchicine, revacept, and therapies targeting the reperfusion injury salvage kinase pathway, survivor activating factor enhancement, mitochondrial pathways, and angiopoietin-like peptide 4 hold promise for the future.
Topics: Animals; Anti-Inflammatory Agents; Cardiotonic Agents; Humans; Molecular Targeted Therapy; Myocardial Infarction; Myocardial Reperfusion Injury; Platelet Aggregation Inhibitors
PubMed: 32659185
DOI: 10.1080/14656566.2020.1787987 -
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 -
Journal of Visualized Experiments : JoVE Aug 2023After cardiac ischemia, there is often insufficient myocardial perfusion, even if flow has been successfully and completely restored in an upstream artery. This...
After cardiac ischemia, there is often insufficient myocardial perfusion, even if flow has been successfully and completely restored in an upstream artery. This phenomenon, known as the "no-reflow phenomenon," is attributed to coronary microvascular dysfunction and has been associated with poor clinical outcomes. In clinical practice, a reduction in coronary flow reserve (CFR) is frequently used as an indicator of coronary artery disease. CFR is defined as the ratio of the peak flow velocity induced by pharmacologic or metabolic factors to the resting flow velocity. This protocol focused on assessing the dynamic changes in CFR before and after ischemia-reperfusion (IR) using pulse wave Doppler measurements. In this study, normal mice exhibited the ability to increase the peak velocity of coronary blood flow up to two times higher than the resting values under isoflurane stimulation. However, after ischemia-reperfusion, the CFR at 1 h significantly decreased compared to the pre-operation baseline. Over time, the CFR showed gradual recovery, but it remained below the normal level. Despite the preservation of systolic function, early detection of microvascular dysfunction is crucial, and establishing a practical guide could aid doctors in this task, while also facilitating the study of cardiovascular disease progression over time.
Topics: Animals; Mice; Coronary Artery Disease; Myocardial Reperfusion Injury; Myocardial Ischemia; Ischemia; Myocardial Reperfusion; Heart Rate
PubMed: 37677023
DOI: 10.3791/65391 -
European Journal of Pharmacology Sep 2023Excessive autophagy induced by reperfusion is one of the causes of severe myocardial injury. Tanshinone IIA (TSN) protects the myocardium against ischemia/reperfusion...
Excessive autophagy induced by reperfusion is one of the causes of severe myocardial injury. Tanshinone IIA (TSN) protects the myocardium against ischemia/reperfusion (I/R) injury. The mechanism by which the inhibition of excessive autophagy contributes to the myocardial protection by TSN is unclear. The protective effects and mechanisms of TSN were studied in H9c2 cells and rats after anoxia/reoxygenation (A/R)-or I/R-induced myocardial injury. The results showed that after the injury, cell viability decreased, lactate dehydrogenase and caspase 3 activity and apoptosis increased, and autophagy was excessively activated. Further, redox imbalance and energy stress, mitochondrial dysfunction, reduced myocardial function, increased infarct area, and severely damaged morphology were observed in rats. TSN increased 14-3-3η expression and regulated Akt/Beclin1 pathway, inhibited excessive autophagy, and significantly reversed the functional, enzymological and morphological indexes in vivo and in vitro. However, the protective effects of TSN were mimicked by 3-methyladenine (an autophagy inhibitor) and were attenuated by pAD/14-3-3η-shRNA, API-2 (an Akt inhibitor), and rapamycin (an autophagy activator). In conclusion, TSN could increase 14-3-3η expression and regulate Akt/Beclin1 pathway, inhibit excessive autophagy, maintain the mitochondrial function, improve energy supply and redox equilibrium, alleviate apoptosis, and ultimately protect myocardium against I/R injury.
Topics: Rats; Animals; Proto-Oncogene Proteins c-akt; Beclin-1; Myocytes, Cardiac; Myocardial Reperfusion Injury; Myocardium; Apoptosis; Autophagy; Ischemia
PubMed: 37406848
DOI: 10.1016/j.ejphar.2023.175865 -
Clinical and Experimental Pharmacology... Dec 2019The mechanisms of protective action of the neuropeptide galanin and its N-terminal fragments against myocardial ischaemia/reperfusion (I/R) injury remain obscure. The...
The mechanisms of protective action of the neuropeptide galanin and its N-terminal fragments against myocardial ischaemia/reperfusion (I/R) injury remain obscure. The aim of this work was to study effects of a novel peptide agonist of galanin receptors [βAla14, His15]-galanin (2-15) (G1) and the full-length galanin (G2) on energy and antioxidant status of the heart with acute infarction. The peptides were synthesized by the automatic solid phase method using Fmoc technology. Their structure was identified by H-NMR spectroscopy and MALDI-TOF mass spectrometry. Experiments were performed on anaesthetized open-chest rats subjected to myocardial regional ischaemia and reperfusion. Intravenous (iv) administration of optimal doses of peptides G1 and G2 (1.0 and 0.5 mg/kg, respectively, at the onset of reperfusion significantly reduced infarct size (on average by 40% compared with control) and the plasma activity of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH). These effects were associated with augmented preservation of aerobic energy metabolism, increased activity of Cu,Zn superoxide dismutase (Cu,Zn-SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) and decreased lipid peroxidation in the area at risk (AAR) at the end of reperfusion. Peptide G1 showed more efficient recovery of the majority of metabolic and antioxidant parameters. The results provide evidence that the galaninergic system can be considered a promising target to reduce energy dysregulation and oxidative damage in myocardial I/R injury.
Topics: Animals; Antioxidants; Galanin; Heart; Lipid Peroxidation; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Peptide Fragments; Rats; Rats, Wistar; Receptors, Galanin; Signal Transduction
PubMed: 31429479
DOI: 10.1111/1440-1681.13164 -
International Journal of Medical... 2022Reperfusion injury following myocardial ischemia remained a challenge for optimal treatment of myocardial infarction. Ginsenosides Rb (G-Rb), the primary components of... (Review)
Review
Reperfusion injury following myocardial ischemia remained a challenge for optimal treatment of myocardial infarction. Ginsenosides Rb (G-Rb), the primary components of ginsenoside, have been reported to exert cardioprotective effects via numerous mechanisms. G-Rb1 mediate cardioprotective effects via various signaling pathways, including mitochondrial apoptotic pathway, PI3K/Akt/mTOR, HIF-1α and GRF91, RhoA, p38α MAPK, and eNOS. G-Rb2 activates the SIRT-1 pathway, while G-Rb3 promotes both JNK-mediated NF-κB and PERK/Nrf2/HMOX1. Generally, ginsenosides Rb1, 2, and 3 modulates oxidative stress, inflammation, and apoptosis, contributing to the improvement of structural, functional and biochemical parameters. In conclusion, G-Rb, particularly G-Rb1, have vast potential as a supplement in attenuating reperfusion injury. Translation into a clinical trial is warranted to confirm the beneficial effects of G-Rb.
Topics: Animals; Apoptosis; Cardiotonic Agents; Ginsenosides; Inflammation; Myocardial Reperfusion Injury; Oxidative Stress; Signal Transduction
PubMed: 34975299
DOI: 10.7150/ijms.64984 -
European Journal of Pharmacology May 2021Reperfusion causes undesirable damage to the ischemic myocardium while restoring the blood flow. In this study, we evaluated the effects of dexpramipexole (DPX) on...
Reperfusion causes undesirable damage to the ischemic myocardium while restoring the blood flow. In this study, we evaluated the effects of dexpramipexole (DPX) on myocardial injury induced by ischemia/reperfusion (I/R) in-vivo and the hypoxia/reoxygenation (HR) in-vitro and examined the functional mechanisms of DPX. DPX protected cells against H/R-induced mitochondrial dysfunction and prevented H/R damage. Both myocardial infarct size and tissue damage due to I/R was reduced upon DPX treatment. We discovered that DPX enhanced mitophagy in-vivo and in-vitro, which was accompanied by enhanced expression of PINK1 and Parkin. Knock-down of PINK1 and Parkin by specific siRNAs reversed DPX-induced inhibition of myocardial I/R injury. These findings suggest that DPX might protect against myocardial injury via PINK1 and Parkin.
Topics: Animals; Cells, Cultured; Disease Models, Animal; Male; Mice, Inbred C57BL; Mitochondria, Heart; Mitophagy; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Pramipexole; Protein Kinases; Protein Transport; Rats, Sprague-Dawley; Signal Transduction; Ubiquitin-Protein Ligases; Mice; Rats
PubMed: 33610599
DOI: 10.1016/j.ejphar.2021.173962