RESUMEN
Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.
Asunto(s)
Acetilcisteína , Antioxidantes , Ácido Ascórbico , Deferoxamina , Daño por Reperfusión Miocárdica , Estrés Oxidativo , Humanos , Antioxidantes/farmacocinética , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Antioxidantes/farmacología , Masculino , Acetilcisteína/administración & dosificación , Acetilcisteína/farmacocinética , Acetilcisteína/efectos adversos , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/efectos adversos , Adulto , Estrés Oxidativo/efectos de los fármacos , Femenino , Deferoxamina/farmacocinética , Deferoxamina/administración & dosificación , Deferoxamina/efectos adversos , Voluntarios Sanos , Adulto Joven , Infusiones Intravenosas , Persona de Mediana Edad , Método Doble Ciego , Quimioterapia Combinada , Biomarcadores/sangreRESUMEN
Mild hyperbaric oxygen therapy (mHBOT) is an adjuvant therapy used in conditions where tissue oxygenation is reduced and is implemented using pressures less than 1.5 ATA and 100% O2 (instead of the classical HBOT at 1.9-3 ATA) which results in cheaper, easier to implement, and equally effective. mHBOT is offered for wellness and beauty and as an anti-aging strategy, in spite of the absence of studies on the cardiovascular system. Consequently, we investigated the impact of mHBOT on the cardiovascular system. Mechanical and energetic parameters of isolated heart submitted to ischemia/reperfusion injury and arterial contractile response from mHBOT-exposed rats were evaluated. In the heart, mHBOT increased pre-ischemic velocity of contraction and ischemic end-diastolic pressure and developed pressure and contractile economy during reperfusion. mHBOT decreased infarct size and increased the plasma nitrite levels. In the artery, mHBOT increased acetylcholine sensitivity. mHBOT protects the heart during ischemia/reperfusion and affects vascular relaxation.
Asunto(s)
Oxigenoterapia Hiperbárica , Daño por Reperfusión Miocárdica , Ratas Wistar , Vasodilatación , Animales , Oxigenoterapia Hiperbárica/métodos , Ratas , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Corazón/fisiología , Corazón/fisiopatología , Contracción MiocárdicaRESUMEN
BACKGROUND: Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear. METHODS: For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1). RESULTS: The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker. CONCLUSIONS: This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.
Asunto(s)
Biología Computacional , Daño por Reperfusión Miocárdica , Animales , Daño por Reperfusión Miocárdica/genética , Ratones , Regulación hacia Abajo/genética , Masculino , Modelos Animales de Enfermedad , Regulación hacia Arriba , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica/métodos , Piruvato Deshidrogenasa (Lipoamida)/genética , Biomarcadores/análisis , Acetiltransferasas/genéticaRESUMEN
BACKGROUND: It has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death. OBJECTIVE: To examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model. METHODS: Isolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca2+ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis. RESULTS: AR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR. CONCLUSIONS: Our data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.
Asunto(s)
Óxido Nítrico , Animales , Concentración de Iones de Hidrógeno , Óxido Nítrico/metabolismo , Masculino , Ratas , Ratas Wistar , Óxido Nítrico Sintasa de Tipo III/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/tratamiento farmacológico , NG-Nitroarginina Metil Éster/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Óxido Nítrico Sintasa/metabolismoRESUMEN
Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.
Asunto(s)
Arritmias Cardíacas , Daño por Reperfusión Miocárdica , Ratas Wistar , Animales , Ratas , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Masculino , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/fisiopatología , Diástole/fisiología , Cloruro de Sodio Dietético/efectos adversos , Frecuencia Cardíaca/fisiologíaRESUMEN
25-hydroxycholesterol (25-HC) plays a role in the regulation of cell survival and immunity. However, the effect of 25-HC on myocardial ischemia/reperfusion (MI/R) injury remains unknown. Our present study aimed to investigate whether 25-HC aggravated MI/R injury through NLRP3 inflammasome-mediated pyroptosis. The overlapping differentially expressed genes (DEGs) in MI/R were identified from the GSE775, GSE45818, GSE58486, and GSE46395 datasets in Gene Expression Omnibus (GEO) database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the database of Annotation, Visualization and Integration Discovery (DAVID). The protein-protein interaction (PPI) network of the overlapping DEGs was established using the Search Tool for the Retrieval of Interacting Genes (STRING) database. These bioinformatics analyses indicated that cholesterol 25-hydroxylase (CH25H) was one of the crucial genes in MI/R injury. The oxygen-glucose deprivation/reoxygenation (OGD/R) cell model was established to simulate MI/R injury. Western blot and RT-qPCR analysis demonstrated that CH25H was significantly upregulated in OGD/R-stimulated H9C2 cardiomyocytes. Moreover, knockdown of CH25H inhibited the OGD/R-induced pyroptosis and nod-like receptor protein 3 (NLRP3) inflammasome activation, as demonstrated by cell counting kit-8 (CCK8), lactate dehydrogenase (LDH), RT-qPCR, and western blotting assays. Conversely, 25-HC, which is synthesized by CH25H, promoted activation of NLRP3 inflammasome in OGD/R-stimulated H9C2 cardiomyocytes. In addition, the NLRP3 inhibitor BAY11-7082 attenuated 25-HC-induced H9C2 cell injury and pyroptosis under OGD/R condition. In conclusion, 25-HC could aggravate OGD/R-induced pyroptosis through promoting activation of NLRP3 inflammasome in H9C2 cells.
Asunto(s)
Glucosa , Hidroxicolesteroles , Inflamasomas , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Ratas , Western Blotting , Glucosa/metabolismo , Hidroxicolesteroles/metabolismo , Hidroxicolesteroles/farmacología , Inflamasomas/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Oxígeno/metabolismo , Piroptosis/fisiologíaRESUMEN
OBJECTIVE: This study aimed to investigate the effect of Esketamine (ESK) on the Hypoxia/Reoxygenation (H/R) injury of cardiomyocytes by regulating TRPV1 and inhibiting the concentration of intracellular Ca2+. METHODS: The H/R injury model of H9c2 cardiomyocytes was established after 4h hypoxia and 6h reoxygenation. H9c2 cells were treated with different concentrations of ESK or TRPV1 agonist capsaicin (10 µM) or TRPV1 inhibitor capsazepine (1 µM). Cell viability was detected by CCK-8 method, and apoptosis by flow cytometry. Intracellular Ca2+ concentration was evaluated by Fluo-4 AM. LDH, MDA, SOD, and GSH-Px were detected with corresponding commercial kits. TRPV1 and p-TRPV1 proteins were detected by Western blot. RESULTS: After H/R, H9c2 cell viability decreased, apoptosis increased, intracellular Ca2+ concentration increased, LDH and MDA levels increased, SOD and GSH-Px levels decreased, and p-TRPV1 expression increased. ESK treatment rescued these changes induced by H/R. After up-regulating TRPV1, the protective effect of ESK on H/R injury of H9c2 cells was weakened, while down-regulating TRPV1 could further protect against H/R injury. CONCLUSION: ESK alleviates H/R injury of cardiomyocytes by regulating TRPV1 expression and inhibiting intracellular Ca2+ concentration.
Asunto(s)
Apoptosis , Calcio , Capsaicina/análogos & derivados , Supervivencia Celular , Ketamina , Miocitos Cardíacos , Canales Catiónicos TRPV , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Animales , Ketamina/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Ratas , Capsaicina/farmacología , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Citometría de Flujo , Estrés Oxidativo/efectos de los fármacos , Western BlottingRESUMEN
PURPOSE: To investigate the protective effect of breviscapine on myocardial ischemia-reperfusion injury (MIRI) in diabetes rats. METHODS: Forty rats were divided into control, diabetes, MIRI of diabetes, and treatment groups. The MIRI of diabetes model was established in the latter two groups. Then, the treatment group was treated with 100 mg/kg breviscapine by intraperitoneal injection for 14 consecutive days. RESULTS: After treatment, compared with MIRI of diabetes group, in treatment group the serum fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance, and glycosylated hemoglobin levels decreased, the serum total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol levels decreased, the serum high-density lipoprotein cholesterol level increased, the heart rate decreased, the mean arterial pressure, left ventricular ejection fraction, and fractional shortening increased, the serum cardiac troponin I, and creatine kinase-MB levels decreased, the myocardial tumor necrosis factor α and interleukin-6 levels decreased, the myocardial superoxide dismutase level increased, and the myocardial malondialdehyde level decreased (all P < 0.05). CONCLUSIONS: For treating MIRI of diabetes in rats, the breviscapine can reduce the blood glucose and lipid levels, improve the cardiac function, reduce the myocardial injury, and decrease the inflammatory response and oxidative stress, thus exerting the alleviating effect.
Asunto(s)
Diabetes Mellitus , Flavonoides , Daño por Reperfusión Miocárdica , Animales , Ratas , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Glucemia , Volumen Sistólico , Función Ventricular Izquierda , ColesterolRESUMEN
Thioredoxin-1 (Trx1) has cardioprotective effects on ischemia/reperfusion (I/R) injury, although its role in ischemic postconditioning (PostC) in middle-aged mice is not understood. This study aimed to evaluate if combining two cardioprotective strategies, such as Trx1 overexpression and PostC, could exert a synergistic effect in reducing infarct size in middle-aged mice. Young or middle-aged wild-type mice (Wt), transgenic mice overexpressing Trx1, and dominant negative (DN-Trx1) mutant of Trx1 mice were used. Mice hearts were subjected to I/R or PostC protocol. Infarct size, hydrogen peroxide (H2O2) production, protein nitration, Trx1 activity, mitochondrial function, and Trx1, pAkt and pGSK3ß expression were measured. PostC could not reduce infarct size even in the presence of Trx1 overexpression in middle-aged mice. This finding was accompanied by a lack of Akt and GSK3ß phosphorylation, and Trx1 expression (in Wt group). Trx1 activity was diminished and H2O2 production and protein nitration were increased in middle-age. The respiratory control rate dropped after I/R in Wt-Young and PostC restored this value, but not in middle-aged groups. Our results showed that Trx1 plays a key role in the PostC protection mechanism in young but not middle-aged mice, even in the presence of Trx1 overexpression.
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Poscondicionamiento Isquémico , Daño por Reperfusión Miocárdica , Animales , Ratones , Peróxido de Hidrógeno , Infarto , Ratones Transgénicos , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMEN
Heart failure is a health problem worldwide. There are some drugs for it, including digoxin, spironolactone, captopril, and valsartan, but some of these drugs can produce secondary effects, such as arrhythmia, cough, hyperkalemia, hyponatremia and hypotension. The aim of this research was to evaluate the biological activity of coumarin (2H-chromen-2-one) and its derivatives (3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, 4-Me-7-Ph-C and 6Br-3-D-C) against ischemia/reperfusion injury as a therapeutic alternative for heart failure. In addition, the biological activity of the coumarin derivative 4-Me-7-Ph-C on left ventricular pressure (LVP) was determined in the absence or presence of ouabain and nifedipine at a dose of 1 nM using an isolated rat heart model. The results showed that i) the coumarin derivative 4-Me-7-Ph-C significantly decreased the infarct area (p+=+0.05) compared with 3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, and 6Br-3-D-C; and ii) 4-Me-7-Ph-C increased LVP in a dose-dependent manner, which effect was inhibited by nifedipine. These data suggest that coumarin 4-Me-7-Ph-C may act as a type-L calcium channel activator, so it could be a good agent to treat heart failure.
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Insuficiencia Cardíaca , Daño por Reperfusión Miocárdica , Ratas , Animales , Nifedipino/farmacología , Nifedipino/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Cumarinas/farmacología , Cumarinas/uso terapéutico , Isquemia , CorazónRESUMEN
Despite significant therapeutic advancements, morbidity and mortality following myocardial infarction (MI) remain unacceptably high. This clinical challenge is primarily attributed to two significant factors: delayed reperfusion and the myocardial injury resulting from coronary reperfusion. Following reperfusion, there is a rapid intracellular pH shift, disruption of ionic balance, heightened oxidative stress, increased activity of proteolytic enzymes, initiation of inflammatory responses, and activation of several cell death pathways, encompassing apoptosis, necroptosis, and pyroptosis. The inflammatory cell death or pyroptosis encompasses the activation of the intracellular multiprotein complex known as the NLRP3 inflammasome. High-density lipoproteins (HDL) are endogenous particles whose components can either promote or mitigate the activation of the NLRP3 inflammasome. In this comprehensive review, we explore the role of inflammasome activation in the context of MI and provide a detailed analysis of how HDL can modulate this process.
Asunto(s)
Infarto del Miocardio , Daño por Reperfusión Miocárdica , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Apoptosis , PiroptosisRESUMEN
Purpose: To investigate the protective effect of breviscapine on myocardial ischemia-reperfusion injury (MIRI) in diabetes rats. Methods: Forty rats were divided into control, diabetes, MIRI of diabetes, and treatment groups. The MIRI of diabetes model was established in the latter two groups. Then, the treatment group was treated with 100 mg/kg breviscapine by intraperitoneal injection for 14 consecutive days. Results: After treatment, compared with MIRI of diabetes group, in treatment group the serum fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance, and glycosylated hemoglobin levels decreased, the serum total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol levels decreased, the serum high-density lipoprotein cholesterol level increased, the heart rate decreased, the mean arterial pressure, left ventricular ejection fraction, and fractional shortening increased, the serum cardiac troponin I, and creatine kinase-MB levels decreased, the myocardial tumor necrosis factor α and interleukin-6 levels decreased, the myocardial superoxide dismutase level increased, and the myocardial malondialdehyde level decreased (all P < 0.05). Conclusions: For treating MIRI of diabetes in rats, the breviscapine can reduce the blood glucose and lipid levels, improve the cardiac function, reduce the myocardial injury, and decrease the inflammatory response and oxidative stress, thus exerting the alleviating effect.
Asunto(s)
Animales , Ratas , Daño por Reperfusión Miocárdica , Estrés Oxidativo , Diabetes Mellitus , Inflamación , IsquemiaRESUMEN
Introducción: La enfermedad por coronavirus ha causado daño miocárdico, razón que ha impactado en las ciencias médicas por lo que ha sido motivo de investigación. Objetivo: Mostrar a través de resultados de recientes investigaciones, los mecanismos mediante los cuales el virus SARS-CoV-2 produce daño miocárdico en los pacientes afectados por la COVID-19, y su influencia en el pronóstico a corto y largo plazo. Métodos: Se realizó una búsqueda bibliográfica de la literatura médica actualizada sobre el tema publicada en idioma inglés y español, indexado en varias bases de datos en el período comprendido de mayo de 2019 a mayo de 2022. De un total de 198 artículos en la revisión, cumplieron con los criterios de selección 78 artículos. Se excluyeron los que no contenían información precisa en cuanto al daño miocárdico provocado por el SARS-CoV-2. Resultados: Se han descrito varios mecanismos que pueden ser los desencadenantes entre los que se destacan: daño directo por angiotensina II, lesión inducida por hipoxia, daño microvascular miocárdico y síndrome de respuesta inflamatoria sistémica. Conclusiones: Los diferentes mecanismos por los cuales el virus SARS-CoV-2 produce daño miocárdico, hacen que los pacientes con la COVID-19 tengan más probabilidades de sufrir una lesión miocárdica. Las manifestaciones clínicas en pacientes con la COVID-19 como miocarditis, insuficiencia cardíaca, arritmias cardíacas, síndrome coronario agudo y derrame pericárdico, son más comunes en pacientes con antecedentes de enfermedad cardiovascular que desfavorecen su pronóstico(AU)
Introduction: Coronavirus disease has caused myocardial damage. This reality has impacted medical sciences and it has been the subject of research. Objective: To show, through the results of recent research, the mechanisms by which the SARS-CoV-2 virus produces myocardial damage in patients affected by COVID-19, and its influence on short- and long-term prognosis. Methods: A bibliographic search was carried out of the updated medical literature on the topic published in English and Spanish, indexed in several databases from May 2019 to May 2022. One hundred ninety-eight articles were included in the review, only 78 met the selection criteria. Those that did not contain precise information regarding myocardial damage caused by SARS-CoV-2 were excluded. Results: Several mechanisms have been described as probable triggers, standing out direct damage by angiotensin II, hypoxia-induced injury, myocardial microvascular damage and systemic inflammatory response syndrome. Conclusions: The different mechanisms by which SARS-CoV-2 virus produces myocardial damage make COVID-19 patients more likely to suffer myocardial injury. Clinical manifestations in COVID-19 patients such as myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome and pericardial effusion are more common in patients with history of cardiovascular disease, which do not favors their prognosis(AU)
Asunto(s)
Humanos , Masculino , Femenino , Daño por Reperfusión Miocárdica , Infecciones por Coronavirus/epidemiología , COVID-19/epidemiologíaRESUMEN
BACKGROUND: Dexmedetomidine (DEX), a specific α2-adrenergic receptor agonist, is protective against myocardial ischemia/reperfusion injury (MIRI). However, the association between DEX preconditioning-induced cardioprotection and mitophagy suppression remains unclear. OBJECTIVE: Hence, we aimed to investigate whether DEX preconditioning alleviates MIRI by suppressing mitophagy via α2-adrenergic receptor activation. METHOD: Sixty isolated rat hearts were treated with or without DEX before inducing ischemia and reperfusion; an α2-adrenergic receptor antagonist, yohimbine (YOH), was also administered before ischemia, alone or with DEX. The heart rate (HR), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximal and minimal rate of left ventricular pressure development (±dp/dtmax), and myocardial infarction size were measured. The mitochondrial ultrastructure and autophagosomes were assessed using transmission electron microscopy. Mitochondrial membrane potential and reactive oxygen species (ROS) levels were measured using JC-1 and dichloride hydrofluorescein diacetate assays, respectively. The expression levels of the mitophagy-associated proteins Beclin1, LC3II/I ratio, p62, PINK1, and Parkin were detected by western blotting. RESULTS: Compared with the control group, in the ischemia/reperfusion group, the HR, LVDP, and ±dp/dtmax were remarkably decreased (p< 0.05), whereas LVEDP and infarct sizes were significantly increased (p< 0.05). DEX preconditioning significantly improved cardiac dysfunction reduced myocardial infarction size, maintained mitochondrial structural integrity, increased mitochondrial membrane potential, inhibited autophagosomes formation, and decreased ROS production and Beclin1, LC3II/I ratio, PINK1, Parkin, and p62 expression(p< 0.05). When DEX and YOH were combined, YOH canceled the effect of DEX, whereas the use of YOH alone had no effect. CONCLUSION: Therefore, DEX preconditioning was cardioprotective against MIRI in rats by suppressing mitophagy via α2-adrenergic receptor activation.
FUNDAMENTO: A dexmedetomidina (DEX), um agonista específico do receptor α2-adrenérgico, é protetora contra lesão de isquemia/reperfusão miocárdica (I/R). No entanto, a associação entre a cardioproteção induzida pelo pré-condicionamento DEX e a supressão da mitofagia permanece pouco clara. OBJETIVO: Portanto, nosso objetivo foi investigar se o pré-condicionamento com DEX alivia a I/R, suprimindo a mitofagia via ativação do receptor α2-adrenérgico. MÉTODO: Sessenta corações de ratos isolados foram tratados com ou sem DEX antes de induzir isquemia e reperfusão; um antagonista do receptor α2-adrenérgico, a ioimbina (YOH), também foi administrado antes da isquemia, isoladamente ou com DEX. A frequência cardíaca (FC), pressão diastólica do ventrículo esquerdo (PDVE), pressão diastólica final do ventrículo esquerdo (PDFVE), taxa máxima e mínima de desenvolvimento da pressão ventricular esquerda (±dp/dtmax) e tamanho do infarto do miocárdio foram medidos. A ultraestrutura mitocondrial e as autofagossomas foram avaliadas por microscopia eletrônica de transmissão. O potencial de membrana mitocondrial e os níveis de espécies reativas de oxigênio (ROS) foram medidos usando os ensaios JC-1 e diacetato de diclorodi hidrofluoresceína, respectivamente. Os níveis de expressão das proteínas associadas à mitofagia Beclin1, relação LC3II/I, p62, PINK1 e Parkin foram detectados por western blotting. RESULTADOS: Em comparação com o grupo controle, no grupo isquemia/reperfusão, a FC, PDVE e ±dp/dtmax foram notavelmente diminuídas (p<0,05), enquanto os tamanhos da PDFVE e do infarto aumentaram significativamente (p<0,05). O pré-condicionamento com DEX melhorou significativamente a disfunção cardíaca, reduziu o tamanho do infarto do miocárdio, manteve a integridade estrutural mitocondrial, aumentou o potencial de membrana mitocondrial, inibiu a formação de autofagossomas e diminuiu a produção de ROS e a relação Beclin1, relação LC3II/I, expressão PINK1, Parkin e p62(p<0,05). Quando DEX e YOH foram combinados, o YOH cancelou o efeito da DEX, enquanto o uso de YOH sozinha não teve efeito. CONCLUSÃO: Portanto, o pré-condicionamento DEX foi cardioprotetor contra I/R em ratos, suprimindo a mitofagia por meio da ativação do receptor α2-adrenérgico.
Asunto(s)
Dexmedetomidina , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Daño por Reperfusión , Ratas , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Beclina-1 , Mitofagia , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/prevención & control , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas , Receptores AdrenérgicosRESUMEN
PURPOSE: It has been explored that sevoflurane (Sevo) is cardioprotective in myocardial ischemia/reperfusion injury (MI/RI) and mediates microRNA (miRNA) expression that control various physiological systems. Enlightened by that, the work was programmed to decode the mechanism of Sevo and miR-99a with the participation of bromodomain-containing protein 4 (BRD4). METHODS: MI/RImodel was established on mice. MI/RI modeled mice were exposed to Sevo or injected with miR-99a or BRD4-related vectors to identify their functions in cardiac function, pathological injury, cardiomyocyte apoptosis, inflammation, and oxidative stress in MI/RI mice. MiR-99a and BRD4 expression in myocardial tissues were tested, and their relation was further validated. RESULTS: MiR-99a was down-regulated, and BRD4 was up-regulated in MI/RI mice. Sevo up-regulated miR-99a to inhibit BRD4 expression in myocardial tissues of MI/RI mice. Sevo improved cardiac function, relieved myocardial injury, repressed cardiomyocyte apoptosis, and alleviated inflammation and oxidative stress in mice with MI/RI. MiR-99a restoration further enhanced the positive effects of Sevo on mice with MI/RI. Overexpression of BRD4 reversed up-regulation of miR-99a-induced attenuation of MI/RI in mice. CONCLUSIONS: The work delineated that Sevo up-regulates miR-99a to attenuate MI/RI by inhibiting BRD4.
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MicroARNs , Daño por Reperfusión Miocárdica , Animales , Ratones , Apoptosis , Inflamación/patología , MicroARNs/genética , MicroARNs/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/farmacología , Sevoflurano/farmacología , Factores de Transcripción/metabolismo , Factores de Transcripción/farmacologíaRESUMEN
Different degrees in the biological activities of Canavalia rosea had been previously reported . In this study, our group assessed the cardioprotective effects of the ethyl acetate fraction (EAcF) of the Canavalia rosea leaves. Firstly, it was confirmed, by in vitro approach, that the EAcF has high antioxidant properties due to the presence of important secondary metabolites, as flavonoids. In order to explore their potential protector against cardiovascular disorders, hearts were previously perfused with EAcF (300 µg.mL-1) and submitted to the global ischemia followed by reperfusion in Langendorff system. The present findings have demonstrated that EAcF restored the left ventricular developed pressure and decreased the arrhythmias severity index. Furthermore, EAcF significantly increased the glutathiones peroxidase activity with decreased malondialdehyde and creatine kinase levels. EAcF was effective upon neither the superoxide dismutase, glutationes reductase nor the catalase activities. In addition, the Western blot analysis revealed that ischemia-reperfusion injury significantly upregulates caspase 3 protein expression, while EAcF abolishes this effect. These results provide evidence that the EAcF reestablishes the cardiac contractility and prevents arrhythmias; it is suggested that EAcF could be used to reduce injury caused by cardiac reperfusion. However more clinical studies should be performed, before applying it in the clinic.
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Antioxidantes , Daño por Reperfusión Miocárdica , Ratas , Animales , Humanos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Canavalia/metabolismo , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Hojas de la Planta/metabolismo , Miocardio/metabolismoRESUMEN
PURPOSE: Remote ischemic preconditioning (RIPC) confers cardioprotection against ischemia reperfusion (IR) injury. However, the precise mechanisms involved in RIPC-induced cardioprotection are not fully explored. The present study was aimed to identify the role of melatonin in RIPC-induced late cardioprotective effects in rats and to explore the role of H2S, TNF-α and mitoKATP in melatonin-mediated effects in RIPC. METHODS: Wistar rats were subjected to RIPC in which hind limb was subjected to four alternate cycles of ischemia and reperfusion of 5 min duration by using a neonatal blood pressure cuff. After 24 h of RIPC or ramelteon-induced pharmacological preconditioning, hearts were isolated and subjected to IR injury on the Langendorff apparatus. RESULTS: RIPC and ramelteon preconditioning protected the hearts from IR injury and it was assessed by a decrease in LDH-1, cTnT and increase in left ventricular developed pressure (LVDP). RIPC increased the melatonin levels (in plasma), H2S (in heart) and decreased TNF-α levels. The effects of RIPC were abolished in the presence of melatonin receptor blocker (luzindole), ganglionic blocker (hexamethonium) and mitochondrial KATP blocker (5-hydroxydecanoic acid). CONCLUSIONS: RIPC produce delayed cardioprotection against IR injury through the activation of neuronal pathway, which may increase the plasma melatonin levels to activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2S levels. Ramelteon-induced pharmacological preconditioning may also activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2S levels.
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Precondicionamiento Isquémico Miocárdico , Precondicionamiento Isquémico , Melatonina , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Ratas , Animales , Infarto del Miocardio/metabolismo , Melatonina/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Wistar , Transducción de Señal , Isquemia , Canales KATP/metabolismo , Canales KATP/farmacologíaRESUMEN
AIM: To investigate the effect of acute treatment with the anabolic steroid (AS) nandrolone decanoate in mitochondrial homeostasis and JAK-STAT3 signaling during the progression of cardiac ischemia/reperfusion injury (IR). METHODS: Male Wistar rats (2 months old) were randomly allocated into four experimental groups: Control (CTRL), IR, AS, and AS + AG490. All animals were euthanized 3 days after a single intramuscular injection of nandrolone at 10 mg/kg (AS and AS + AG490 groups) or vehicle (CTRL and IR groups). Baseline mRNA expression of antioxidant enzymes superoxide dismutase (SOD) 1 and 2, glutathione peroxidase, catalase, and myosin heavy chain (MHC) α and ß were compared between CTRL and AS groups. Isolated hearts were submitted to ex vivo ischemia and reperfusion, except for hearts from the CTRL group. Before the IR protocol, the JAK-STAT3 inhibitor AG490 was perfused in hearts from the AS + AG490 group. Heart samples were collected during reperfusion to investigate the effects on mitochondrial function. Results Antioxidant enzyme mRNA expression was unaffected, whereas the AS group exhibited decreased ß- MHC/α-MHC ratio versus the CTRL group. Compared to the IR group, the AS group exhibited better recovery of post-ischemic left ventricular (LV) end-diastolic pressure and LV-developed pressure levels, while infarct size significantly decreased. Furthermore, mitochondrial production, transmembrane potential, and swelling were improved, whereas ROS formation was decreased versus the IR group. These effects were prevented by the perfusion of JAK-STAT3 inhibitor AG490. CONCLUSION: These findings suggest that acute nandrolone treatment can provide cardioprotection by recruiting the JAK-STAT3 signaling pathway and mitochondrial preservation.
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Daño por Reperfusión Miocárdica , Nandrolona , Ratas , Animales , Masculino , Antioxidantes , Ratas Wistar , Mitocondrias/metabolismo , ARN MensajeroRESUMEN
PURPOSE: Myocardial ischemia/reperfusion injury (MIRI) leads to myocardial tissue necrosis, which will increase the size of myocardial infarction. The study examined the protective effect and mechanism of the Guanxin Danshen formula (GXDSF) on MIRI in rats. METHODS: MIRI model was performed in rats; rat H9C2 cardiomyocytes were hypoxia-reoxygenated to establish a cell injury model. RESULTS: The GXDSF significantly reduced myocardial ischemia area, reduced myocardial structural injury, decreased the levels of interleukin (IL-1ß, IL-6) in serum, decreased the activity of myocardial enzymes, increased the activity of superoxide dismutase (SOD), and reduced glutathione in rats with MIRI. The GXDSF can reduce the expression of nucleotide- binding oligomerization domain, leucine-rich repeat and pyrin domain containing nod-like receptor family protein 3 (NLRP3), IL-1ß, caspase-1, and gasdermin D (GSDMD) in myocardial tissue cells. Salvianolic acid B and notoginsenoside R1 protected H9C2 cardiomyocytes from hypoxia and reoxygenation injury and reduced the levels of tumor necrosis factor α (TNF-α) and IL-6 in the cell supernatant, decreasing the NLRP3, IL-18, IL-1ß, caspase-1, and GSDMD expression in H9C2 cardiomyocytes. GXDSF can reduce the myocardial infarction area and alleviate the damage to myocardial structure in rats with MIRI, which may be related to the regulation of the NLRP3. CONCLUSIONS: GXDSF reduces MIRI in rat myocardial infarction injury, improves structural damage in myocardial ischemia injury, and reduces myocardial tissue inflammation and oxidative stress by lowering inflammatory factors and controlling focal cell death signaling pathways.
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Infarto del Miocardio , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Salvia miltiorrhiza , Ratas , Animales , Ratas Sprague-Dawley , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-6/metabolismo , Salvia miltiorrhiza/metabolismo , Miocitos Cardíacos/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/prevención & control , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Caspasa 1 , Hipoxia/metabolismoRESUMEN
OBJECTIVE: To explore the effect of ischemic postconditioning on myocardial ischemia-reperfusion-induced acute lung injury (ALI). METHODS: Forty adult male C57BL/6 mice were randomly divided into sham operation group (SO group), myocardial ischemia-reperfusion group (IR group), ischemic preconditioning group (IPRE group) and ischemic postconditioning group (IPOST group) (10 mice in each group). Anterior descending coronary artery was blocked for 60 min and then reperfused for 15 min to induce myocardial IR. For the IPRE group, 3 consecutive cycles of 5 min of occlusion and 5 minutes of reperfusion of the coronary arteries were performed before ischemia. For the IPOST group, 3 consecutive cycles of 5 min reperfusion and 5 minutes of occlusion of the coronary arteries were performed before reperfusion. Pathological changes of lung tissue, lung wet-to-dry (W/D) weight ratio, inflammatory factors, oxidative stress indicators, apoptosis of lung cells and endoplasmic reticulum stress (ERS) protein were used to evaluate lung injury. RESULTS: After myocardial IR, lung injury worsened significantly, manifested by alveolar congestion, hemorrhage, structural destruction of alveolar septal thickening, and interstitial neutrophil infiltration. In addition, lung W/D ratio was increased, plasma inflammatory factors, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17A, were increased, malondialdehyde (MDA) activity of lung tissue was increased, and superoxide dismutase (SOD) activity was decreased after myocardial IR. It was accompanied by the increased protein expression levels of ERS-related protein glucose regulatory protein 78 (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and caspase-12, and the increased apoptotic indices of lung tissues. CONCLUSION: IPOST can effectively improve myocardial IR-induced ALI by inhibiting ERS-induced apoptosis of alveolar epithelial cells.