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Anastatin Derivatives Alleviate Myocardial Ischemia-Reperfusion Injury via Antioxidative Properties.Molecules (Basel, Switzerland) Aug 2021(±)-Anastatins A and B are flavonoids isolated from . In a previous study, twenty-four di- and tri-substituted novel derivatives of anastatins were designed and their...
(±)-Anastatins A and B are flavonoids isolated from . In a previous study, twenty-four di- and tri-substituted novel derivatives of anastatins were designed and their preliminary antioxidant activities were evaluated. In the present study, the protective effect of myocardial ischemia-reperfusion (I/R) and the systematic antioxidant capacity of 24 derivatives were further studied. Compound was the most potent among all the compounds studied, which increased the survival of H9c2 cells to 80.82%. The antioxidant capability of compound was evaluated in ferric reducing antioxidant power, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging, and 2,2-diphenyl-1-picrylhydrazyl assays. It was observed that compound significantly reduced infarcted areas and improved histopathological and electrocardiogram changes in rats with myocardial I/R injury. Moreover, compound decreased the leakage rates of serum lactate dehydrogenase, creatine kinase, and malonyldialdehyde from rat myocardial tissues and increased the level of glutathione and superoxide dismutase activities following myocardial I/R injury in rats. Taken together, we concluded that compound had potent cardioprotective effects against myocardial I/R injury both in vitro and in vivo owing to its extensive antioxidant activities.
Topics: Animals; Antioxidants; Apoptosis; Cell Survival; Flavonoids; Glutathione; Male; Malondialdehyde; Myocardial Reperfusion Injury; Oxidative Stress; Rats
PubMed: 34443365
DOI: 10.3390/molecules26164779 -
Journal of the American Heart... Jun 2021Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia-reperfusion (IR) injury, which hampers... (Comparative Study)
Comparative Study
Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia-reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle-mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C-C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30-45 minutes) after reperfusion, whereas C-C chemokine receptor 2 contributes to IR injury at later time point (45-60 minutes) after reperfusion. Double deficiency of CypD and C-C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C-C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly-6C monocytes after myocardial IR injury. In CypD-knockout mice, administration of interleukin-1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly-lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte-mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle-mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.
Topics: Animals; Anti-Inflammatory Agents; Peptidyl-Prolyl Isomerase F; Cyclosporine; Disease Models, Animal; Drug Carriers; Drug Combinations; Drug Compounding; Inflammation Mediators; Interleukin-1beta; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Mitochondrial Permeability Transition Pore; Myocardial Reperfusion Injury; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Quinolines; Receptors, CCR2; Time Factors; Mice
PubMed: 34056918
DOI: 10.1161/JAHA.120.019521 -
Molecular Medicine Reports Apr 2022Myocardial ischemia/reperfusion (MI/RI) syndrome is one of the leading causes of mortality and disability. Propofol postconditioning is known to improve myocardial...
Myocardial ischemia/reperfusion (MI/RI) syndrome is one of the leading causes of mortality and disability. Propofol postconditioning is known to improve myocardial ischemia/reperfusion injury (MI/RI). The present study aimed to explore the mechanism of propofol postconditioning in diabetic MI/RI. Diabetic MI/RI rat models were established and the rats were treated via propofol postconditioning. Staining with 2,3,5‑triphenyl‑2H‑tetrazolium chloride, H&E staining, TUNEL staining and ELISA were applied to detect infarct size, pathological changes, apoptosis and oxidative stress‑related factor and apoptotic factor levels, respectively. Subsequently, the effect of propofol on H9C2 cells was also assessed using the Cell Counting Kit‑8 assay. High‑glucose hypoxia/reperfusion (H/R) models of H9C2 cardiomyocytes were established. miR‑200c‑3p overexpression or AdipoR2 silencing combined with propofol postconditioning was performed in H/R‑induced H9C2 cells and STAT3 protein expression levels were determined. Propofol postconditioning significantly reduced myocardial infarct size, oxidative stress and apoptosis in diabetic MI/RI models. Furthermore, propofol postconditioning significantly reduced the oxidative stress and apoptosis of H9C2 cells in high‑glucose H/R models. Propofol postconditioning also significantly downregulated miR‑200c‑3p expression levels and promoted AdipoR2 expression levels. miR‑200c‑3p overexpression or AdipoR2 downregulation significantly reversed the effects of propofol postconditioning on its antioxidation and anti‑apoptotic effects in H9C2 cells and on decreasing STAT3 phosphorylation levels. Together, the results of the present study demonstrated that propofol postconditioning inhibited miR‑200c‑3p, upregulated AdipoR2 and activated the STAT3 signaling pathway, thus alleviating diabetic MI/RI and therefore highlighting its potential as a treatment of diabetic MI/RI.
Topics: Animals; Apoptosis; Diabetes Mellitus; MicroRNAs; Myocardial Reperfusion Injury; Myocytes, Cardiac; Propofol; Rats; Signal Transduction
PubMed: 35211763
DOI: 10.3892/mmr.2022.12653 -
Cells Oct 2022Myocardial ischemia-reperfusion injury (MIRI) results in the aggravation of myocardial injury caused by rapid recanalization of the ischemic myocardium. In the past few... (Review)
Review
Myocardial ischemia-reperfusion injury (MIRI) results in the aggravation of myocardial injury caused by rapid recanalization of the ischemic myocardium. In the past few years, there is a growing interest in investigating the complex pathophysiological mechanism of MIRI for the identification of effective targets and drugs to alleviate MIRI. Currently, pyroptosis, a type of inflammatory programmed death, has received greater attention. It is involved in the MIRI development in combination with other mechanisms of MIRI, such as oxidative stress, calcium overload, necroptosis, and apoptosis, thereby forming an intertwined association between different pathways that affect MIRI by regulating common pathway molecules. This review describes the pyroptosis mechanism in MIRI and its relationship with other mechanisms, and also highlights non-coding RNAs and non-cardiomyocytes as regulators of cardiomyocyte pyroptosis by mediating associated pathways or proteins to participate in the initiation and development of MIRI. The research progress on novel small molecule drugs, clinical drugs, traditional Chinese medicine, etc. for regulating pyroptosis can play a crucial role in effective MIRI alleviation. When compared to research on other mature mechanisms, the research studies on pyroptosis in MIRI are inadequate. Although many related protective drugs have been identified, these drugs generally lack clinical applications. It is necessary to further explore and verify these drugs to expand their applications in clinical setting. Early inhibition of MIRI by targeted regulation of pyroptosis is a key concern that needs to be addressed in future studies.
Topics: Humans; Myocardial Reperfusion Injury; Pyroptosis; Calcium; Myocytes, Cardiac; Protective Agents
PubMed: 36291138
DOI: 10.3390/cells11203271 -
Bioengineered Dec 2021Myocardial injury caused by ischemia-reperfusion is the main pathological manifestation of coronary artery disease (CAD), which is characterized by high mortality and...
Myocardial injury caused by ischemia-reperfusion is the main pathological manifestation of coronary artery disease (CAD), which is characterized by high mortality and morbidity. Thus, there's an urgent need to develop efficacious strategies and elucidate the underlying mechanisms to prevent or alleviate myocardial ischemia-reperfusion injury to improve the clinical outcomes in patients. In this study, we took advantage of a typical myocardial cell line of mice (HL-1) and cultured with or without an aquaporin 4 inhibitor (TGN-20 denoted as AQP4i) under normal conditions (NC), ischemia (IS) and ischemia reperfusion (IR), respectively. The cytomorphology, ultrastructure, cell vitality and expression pattern of apoptotic proteins were verified with scanning electron microscope (SEM), immunofluorescence staining, flow cytometry, quantitative real-time PCR and western-blotting analysis, respectively. HL-1 under IS or IR condition revealed higher expression of Aquaporin 4 (Aqp4) compared to the NC group, whereas showed similarity in cytomorphology and ultrastructure. Aqp4 inhibition was sufficient to improve the apoptotic cells in HL-1 while showed minimal effects to the other cellular vitality. Furthermore, the expression pattern of apoptotic proteins and anti-apoptotic proteins together with proinflammatory factors in HL-1 was effectively rescued by Aqp4i treatment both at the mRNA level and protein level. Ischemia and ischemia reperfusion caused higher expression of Aqp4 and resultant increase of cardiomyocyte pyroptosis. Myocardial ischemia-reperfusion injury of HL-1 was effectively alleviated by Aqp4 and pyroptosis inhibition. Our findings provided new references for myocardial ischemia-reperfusion injury management via targeting Aqp4-mediated pyroptosis of cardiomyocyte.
Topics: Animals; Aquaporin 4; Mice; Myocardial Reperfusion Injury; Myocytes, Cardiac; Pyroptosis
PubMed: 34657556
DOI: 10.1080/21655979.2021.1992332 -
International Journal of Molecular... Apr 2021Myocardial ischemia/reperfusion injury (MIRI) may cause myocardial stunning, reperfusion arrhythmia, no‑reflow phenomenon and lethal reperfusion injury, which has a... (Review)
Review
Myocardial ischemia/reperfusion injury (MIRI) may cause myocardial stunning, reperfusion arrhythmia, no‑reflow phenomenon and lethal reperfusion injury, which has a significant effect on the prognosis of patients undergoing thrombolytic agent therapy and percutaneous coronary intervention. Increasing evidence suggests that apoptosis, innate inflammation, oxidative stress, calcium overload and autophagy are involved in the pathogenesis of MIRI. Recent advancements in RNA sequencing technologies and genome‑wide analyses led to the finding of small non‑coding RNAs (ncRNAs). ncRNAs modulate cellular processes such as signal transduction, transcription, chromatin remodeling and post‑transcriptional modification. The effects of ncRNAs on cellular biology is more considerable than initially expected, and thus ncRNAs have gained increasing attention and focus in modern medical research. There are several types of ncRNAs, such as microRNAs (miRNAs), long non‑coding RNAs (lncRNAs) and circular RNAs (circRNAs), which have been shown to regulate gene expression at the transcription, post‑transcription and epigenetic levels. Dysregulation of ncRNAs, including miRNAs, lncRNAs and circRNAs, may participate in the molecular mechanisms of MIRI. The present review summarizes the characteristics and biological roles of miRNAs, lncRNAs and circRNAs, with particular emphasis on their role in MIRI, which show the novel complexity of ischemic hearts and may offer valuable insights into the pathogenesis of MIRI.
Topics: Genome-Wide Association Study; MicroRNAs; Myocardial Reperfusion Injury; RNA, Circular; RNA, Untranslated
PubMed: 33576444
DOI: 10.3892/ijmm.2021.4875 -
Journal of the American Association For... Sep 2020The porcine ischemia-reperfusion model is one of the most commonly used for cardiology research and for testing interventions for myocardial regeneration. In creating... (Review)
Review
The porcine ischemia-reperfusion model is one of the most commonly used for cardiology research and for testing interventions for myocardial regeneration. In creating ischemic reperfusion injury, the anesthetic protocol is important for assuring hemodynamic stability of the animal during the induction of the experimental lesion and may affect its postoperative survival. This paper reviews the many drugs and anesthetic protocols used in recent studies involving porcine models of ischemiareperfusion injury. The paper also summarizes the most important characteristics of some commonly used anesthetic drugs. Literature was selected for inclusion in this review if the authors described the anesthetic protocol used and also reported the mortality rate attributed to the creation of the model. This information is an important consideration because the anesthetic protocol can influence hemodynamic stability during the experimental induction of an acute myocardial infarction, thereby impacting the survival rate and affecting the number of animals needed for each study.
Topics: Anesthesia; Anesthetics; Animals; Disease Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Swine
PubMed: 32709259
DOI: 10.30802/AALAS-JAALAS-19-000137 -
Journal of the American College of... Aug 2020
Topics: Heart Ventricles; Humans; Myocardial Infarction; Myocardial Reperfusion
PubMed: 32762904
DOI: 10.1016/j.jacc.2020.06.032 -
Stem Cell Research & Therapy Jan 2021Ischemia-reperfusion injury (IRI) is an important factor limiting the success of cardiac reperfusion therapy. Curcumin has a significant cardioprotective effect against...
BACKGROUND
Ischemia-reperfusion injury (IRI) is an important factor limiting the success of cardiac reperfusion therapy. Curcumin has a significant cardioprotective effect against IRI, can inhibit ventricular remodeling induced by pressure load or MI, and improve cardiac function. However, the poor water solubility and low bioavailability of curcumin restrict its clinical application.
METHODS
In this study, we prepared and evaluated a curcumin-hydrogel (cur-hydrogel) to reduce cardiomyocyte apoptosis and reactive oxygen species formation induced by hypoxia-reoxygenation injury, promote autophagy, and reduce mitochondrial damage by maintaining the phosphorylation of Cx43.
RESULTS
Meanwhile, cur-hydrogel can restore cardiac function, inhibit myocardial collagen deposition and apoptosis, and activate JAK2/STAT3 pathway to alleviate myocardial ischemia-reperfusion injury in rats.
CONCLUSIONS
The purpose of this study is to elucidate the protective effects of cur-hydrogel on myocardial ischemia-reperfusion injury by regulating apoptosis, autophagy, and mitochondrial injury in vitro and in vivo, which lays a new theoretical and experimental foundation for the prevention and reduction of IRI.
Topics: Animals; Apoptosis; Autophagy; Curcumin; Hydrogels; Mitochondria; Myocardial Reperfusion Injury; Myocytes, Cardiac; Rats; Reperfusion Injury
PubMed: 33509263
DOI: 10.1186/s13287-020-02101-y -
International Journal of Molecular... Feb 2021Cardiac preconditioning (PC) and postconditioning (PoC) are powerful measures against the consequences of myocardial ischemia and reperfusion (I/R) injury. Mannitol-a...
Cardiac preconditioning (PC) and postconditioning (PoC) are powerful measures against the consequences of myocardial ischemia and reperfusion (I/R) injury. Mannitol-a hyperosmolar solution-is clinically used for treatment of intracranial and intraocular pressure or promotion of diuresis in renal failure. Next to these clinical indications, different organ-protective properties-e.g., perioperative neuroprotection-are described. However, whether Mannitol also confers cardioprotection via a pre- and/or postconditioning stimulus, possibly reducing consequences of I/R injury, remains to be seen. Therefore, in the present study we investigated whether (1) Mannitol-induced pre- and/or postconditioning induces myocardial infarct size reduction and (2) activation of mitochondrial ATP-sensitive potassium (mK) channels is involved in cardioprotection by Mannitol. Experiments were performed on isolated hearts of male Wistar rats via a pressure controlled Langendorff system, randomized into 7 groups. Each heart underwent 33 min of global ischemia and 60 min of reperfusion. Control hearts (Con) received Krebs-Henseleit buffer as vehicle only. Pre- and postconditioning was achieved by administration of 11 mmol/L Mannitol for 10 min before ischemia (Man-PC) or immediately at the onset of reperfusion (Man-PoC), respectively. In further groups, the mK channel blocker 5HD, was applied with and without Mannitol, to determine the potential underlying cardioprotective mechanisms. Primary endpoint was infarct size, determined by triphenyltetrazolium chloride staining. Mannitol significantly reduced infarct size both as a pre- (Man-PC) and postconditioning (Man-PoC) stimulus compared to control hearts (Man-PC: 31 ± 4%; Man-PoC: 35 ± 6%, each < 0.05 vs. Con: 57 ± 9%). The mK channel inhibitor completely abrogated the cardioprotective effect of Mannitol-induced pre- (5HD-PC-Man-PC: 59 ± 8%, < 0.05 vs. Man-PC) and postconditioning (5HD-PoC-Man-PoC: 59 ± 10% vs. < 0.05 Man-PoC). Infarct size was not influenced by 5HD itself (5HD-PC: 60 ± 14%; 5HD-PoC: 54 ± 14%, each ns vs. Con). This study demonstrates that Mannitol (1) induces myocardial pre- and postconditioning and (2) confers cardioprotection via activation of mK channels.
Topics: Animals; Male; Rats; Cardiotonic Agents; Diuretics, Osmotic; Ischemic Preconditioning, Myocardial; Mannitol; Myocardial Infarction; Myocardial Reperfusion Injury; Potassium Channels; Random Allocation; Rats, Wistar
PubMed: 33673646
DOI: 10.3390/ijms22052395