RESUMEN
Myocardial ischaemia reperfusion injury (IRI) occurring from acute coronary artery disease or cardiac surgical interventions such as bypass surgery can result in myocardial dysfunction, presenting as, myocardial "stunning", arrhythmias, infarction, and adverse cardiac remodelling, and may lead to both a systemic and a localised inflammatory response. This localised cardiac inflammatory response is regulated through the nucleotide-binding oligomerisation domain (NACHT), leucine-rich repeat (LRR)-containing protein family pyrin domain (PYD)-3 (NLRP3) inflammasome, a multimeric structure whose components are present within both cardiomyocytes and in cardiac fibroblasts. The NLRP3 inflammasome is activated via numerous danger signals produced by IRI and is central to the resultant innate immune response. Inhibition of this inherent inflammatory response has been shown to protect the myocardium and stop the occurrence of the systemic inflammatory response syndrome following the re-establishment of cardiac circulation. Therapies to prevent NLRP3 inflammasome formation in the clinic are currently lacking, and therefore, new pharmacotherapies are required. This review will highlight the role of the NLRP3 inflammasome within the myocardium during IRI and will examine the therapeutic value of inflammasome inhibition with particular attention to carbon monoxide, nitric oxide, and hydrogen sulphide as potential pharmacological inhibitors of NLRP3 inflammasome activation.
Asunto(s)
Monóxido de Carbono , Sulfuro de Hidrógeno , Inflamasomas , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Óxido Nítrico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Humanos , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/farmacología , Inflamasomas/metabolismo , Óxido Nítrico/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Animales , Monóxido de Carbono/metabolismo , Gasotransmisores/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patologíaRESUMEN
Remote ischemic preconditioning (RIPC) reduces ischemia-reperfusion injury in aortocoronary bypass surgery, potentially via extracellular vesicles (EVs) and their micro-RNA content. Clinical data implicate that propofol might inhibit the cardioprotective RIPC effect. This prospective, randomized study investigated the influence of different anesthetic regimes on RIPC efficacy and EV micro-RNA signatures. We also assessed the impact of propofol on cell protection after hypoxic conditioning and EV-mediated RIPC in vitro. H9c2 rat cardiomyoblasts were subjected to hypoxia, with or without propofol, and subsequent simulated ischemia-reperfusion injury. Apoptosis was measured by flow cytometry. Blood samples of 64 patients receiving anesthetic maintenance with propofol or isoflurane, along with RIPC or sham procedures, were analyzed, and EVs were enriched using a polymer-based method. Propofol administration corresponded with increased Troponin T levels (4669 ± 435.6 pg/mL), suggesting an inhibition of the cardioprotective RIPC effect. RIPC leads to a notable rise in miR-21 concentrations in the group receiving propofol anesthesia (fold change 7.22 ± 6.6). In vitro experiments showed that apoptosis reduction was compromised with propofol and only occurred in an EV-enriched preconditioning medium, not in an EV-depleted medium. Our study could clinically and experimentally confirm propofol inhibition of RIPC protection. Increased miR-21 expression could provide evidence for a possible inhibitory mechanism.
Asunto(s)
Apoptosis , Enfermedad de la Arteria Coronaria , Vesículas Extracelulares , Propofol , Vesículas Extracelulares/metabolismo , Animales , Propofol/farmacología , Ratas , Humanos , Enfermedad de la Arteria Coronaria/metabolismo , Masculino , Apoptosis/efectos de los fármacos , Precondicionamiento Isquémico/métodos , Femenino , Persona de Mediana Edad , MicroARNs/genética , MicroARNs/metabolismo , Precondicionamiento Isquémico Miocárdico/métodos , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Anciano , Anestésicos/farmacología , Estudios Prospectivos , Línea CelularRESUMEN
ABSTRACT: The role of intravenous immunoglobulin in protecting the diabetic heart from ischemia/reperfusion (I/R) injury is unclear. Hearts isolated from adult diabetic and nondiabetic Wistar rats (n = 8 per group) were treated with intravenous immunoglobulin (IVIG) either 2 hours before euthanasia, before ischemia, or at reperfusion. Hemodynamic data were acquired using the Isoheart software version 1.524-S. Ischemia/reperfusion (I/R) injury was evaluated by 2,3,5-triphenyltetrazolium chloride staining and troponin T levels. The levels of apoptosis markers, caspases-3/8, antioxidant enzymes, superoxide dismutase and catalase, glucose transporters, GLUT-1 and GLUT-4, phosphorylated ERK1/2, and phosphorylated eNOS were estimated by Western blotting. Proinflammatory and anti-inflammatory cytokine levels were evaluated using enzyme-linked immunosorbent assays. Intravenous immunoglobulin administration abolished the effects of I/R injury in hearts subjected to hyperglycemia when infused at reperfusion, before ischemia, or at reperfusion in 4-week diabetic rat hearts and only at reperfusion in 6-week diabetic rat hearts. IVIG infusion resulted in a significant (P < 0.05) recovery of cardiac hemodynamics and decreased infarct size. IVIG also reduced the levels of troponin T, apoptotic enzymes, and proinflammatory cytokines. IVIG significantly (P < 0.05) increased the levels of anti-inflammatory cytokines, antioxidant enzymes, GLUT-4, and phosphorylated eNOS. Intravenous immunoglobulin protected the hearts from I/R injury if infused at reperfusion in the presence of hyperglycemia, in 4- and 6-week diabetic rat hearts, and when infused before ischemia in 4-week diabetic rat hearts. IVIG exerts its cardioprotective effects associated with the upregulated phosphorylated eNOS/GLUT-4 pathway.
Asunto(s)
Diabetes Mellitus Experimental , Transportador de Glucosa de Tipo 4 , Daño por Reperfusión Miocárdica , Óxido Nítrico Sintasa de Tipo III , Ratas Wistar , Transducción de Señal , Animales , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Inmunoglobulinas Intravenosas/farmacología , Apoptosis/efectos de los fármacos , Miocardio/patología , Miocardio/metabolismo , Miocardio/enzimología , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/prevención & control , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/tratamiento farmacológico , Ratas , Estrés Oxidativo/efectos de los fármacos , Citocinas/metabolismo , Preparación de Corazón Aislado , Mediadores de Inflamación/metabolismoRESUMEN
While 3-N-butylphthalide (NBP) has demonstrated notable cardioprotective effects, its precise role in mitigating myocardial arrhythmia following ischemia/reperfusion (IR) injury in diabetes remains unclear. This study aimed to explore the potential mechanisms through which NBP mitigates reperfusion-induced myocardial arrhythmia in diabetic rats, with a particular focus on mitochondrial function and biogenesis, endoplasmic reticulum (ER) stress, and oxidative/inflammatory responses. Sixty Sprague-Dawley rats were divided into non-diabetic and diabetic groups, subjected to in-vivo myocardial IR injury, and treated with NBP (100 mg/kg, intraperitoneally) through different modalities: preconditioning, postconditioning, or a combination of both. Electrocardiography (ECG) was employed to assess the incidence and severity of arrhythmia. Fluorometric, Western blotting and ELISA analyses were utilized to measure the mitochondrial, ER stress, and cellular outcomes. Treatment of non-diabetic rats with NBP in preconditioned, postconditioned, and combined approaches significantly reduced cardiotroponin-I and the frequency and severity of arrhythmias induced by IR injury. However, only the combined preconditioning plus postconditioning approach of NBP had protective and antiarrhythmic effects in diabetic rats, in an additive manner. Moreover, the NBP combined approach improved mitochondrial function and upregulated the expression of PGC-1?, Sirt1, and glutathione while concurrently downregulating ER stress and oxidative and pro-inflammatory-related proteins in diabetic rats. In conclusion, the combined approach of NBP treatment was effective in mitigating myocardial arrhythmia in diabetic rats. This approach coordinates interactions within the mitochondria-endoplasmic reticulum network and inhibits oxidative and inflammatory mediators, offering a promising strategy for managing myocardial arrhythmia in diabetic patients. Key words: Myocardial Infarction, Mitochondria, Arrhythmia, Reperfusion, Diabetes, Ischemia.
Asunto(s)
Arritmias Cardíacas , Benzofuranos , Diabetes Mellitus Experimental , Estrés del Retículo Endoplásmico , Daño por Reperfusión Miocárdica , Estrés Oxidativo , Ratas Sprague-Dawley , Animales , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Masculino , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Ratas , Estrés del Retículo Endoplásmico/efectos de los fármacos , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológicoRESUMEN
Cardiac resident MerTK+ macrophages exert multiple protective roles after ischemic injury; however, the mechanisms regulating their fate are not fully understood. In the present study, we show that the GAS6-inducible transcription factor, activating transcription factor 3 (ATF3), prevents apoptosis of MerTK+ macrophages after ischemia-reperfusion (IR) injury by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Ifnb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK+ cardiac macrophages, poor angiogenesis and worse heart dysfunction after IR, which were rescued by the transfer of MerTK+ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6-ATF3 axis has a protective role against IR injury by regulating MerTK+ cardiac macrophage survival and/or proliferation.
Asunto(s)
Factor de Transcripción Activador 3 , Apoptosis , Proliferación Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intercelular , Macrófagos , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica , Tirosina Quinasa c-Mer , Animales , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Macrófagos/metabolismo , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa c-Mer/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Humanos , Masculino , Ratones Noqueados , Transducción de Señal , Ratones , Células CultivadasAsunto(s)
Factor de Transcripción Activador 3 , Macrófagos , Daño por Reperfusión Miocárdica , Animales , Macrófagos/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patología , Humanos , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Miocardio/patología , Miocardio/metabolismo , RatonesRESUMEN
Brown adipose tissue (BAT) plays a critical role in regulating cardiovascular homeostasis through the secretion of adipokines, such as fibroblast growth factor 21 (FGF21). Dexmedetomidine (DEX) is a selective α2-adrenergic receptor agonist with a protection against myocardial ischemia/reperfusion injury (MI/RI). It remains largely unknown whether or not BAT-derived FGF21 is involved in DEX-induced cardioprotection in the context of MI/RI. Herein, we demonstrated that DEX alleviated MI/RI and improved heart function through promoting the release of FGF21 from interscapular BAT (iBAT). Surgical iBAT depletion or supplementation with a FGF21 neutralizing antibody attenuated the beneficial effects of DEX. AMPK/PGC1α signaling-induced fibroblast growth factor 21 (FGF21) release in brown adipocytes is required for DEX-mediated cardioprotection since blockade of the AMPK/PGC1α axis weakened the salutary effects of DEX. Co-culture experiments showed that DEX-induced FGF21 from brown adipocytes increased the resistance of cardiomyocytes to hypoxia/reoxygenation (H/R) injury via modulating the Keap1/Nrf2 pathway. Our results provided robust evidence that the BAT-cardiomyocyte interaction is required for DEX cardioprotection, and revealed an endocrine role of BAT in DEX-mediating protection of hearts against MIRI.
Asunto(s)
Tejido Adiposo Pardo , Dexmedetomidina , Factores de Crecimiento de Fibroblastos , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Dexmedetomidina/farmacología , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Masculino , Cardiotónicos/farmacología , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Adipocitos Marrones/metabolismo , Adipocitos Marrones/efectos de los fármacosRESUMEN
BACKGROUND: Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. METHODS: ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 µmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. RESULTS: ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. CONCLUSION: ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Homólogo de la Proteína 1 Relacionada con la Autofagia , Autofagia , Chalconas , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Ratas Sprague-Dawley , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Masculino , Ratas , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Línea Celular , Chalconas/farmacología , Modelos Animales de Enfermedad , Fibrosis , Infarto del Miocardio/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/enzimología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
INTRODUCTION: Insufficient supply of cardiac grafts represents a severe obstacle in heart transplantation. Donation after Circulatory Death (DCD), in addition to conventional donation after brain death, is one promising option to overcome the organ shortage. However, DCD organs undergo an inevitable more extended period of warm unprotected ischemia between circulatory arrest and graft procurement. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have shown remarkable protective effects against ischemia-reperfusion injury. Thus, we aimed to enhance grafts preservation from DCD donors, through treatment with MSC-EVs. METHODS: Female pigs were euthanized by barbiturate overdose and after 20â¯min of a flat EKG, the chest was opened, the heart harvested and subsequently connected to an extracorporeal perfusion machine. MSC-EVs, isolated by ion exchange chromatography, were added to the perfusion solution (1×1011 particles) and the heart was perfused for 2â¯h. Then, heart tissue biopsies were taken to assess histological changes, mitochondrial morphology, antioxidant enzyme activity and inflammation mediators' expression. Biochemical parameters of myocardial viability were assessed in the perfusate. RESULTS: The treatment with MSC-EVs significantly prevented mitochondria swelling, mitochondrial cristae loss and oxidative stress in cardiac tissue. The protective effect of MSC-EVs was confirmed by the delayed increase of the cardiac-specific enzymes CK and TnC in the perfusate and the reduction of caspase-3+ cells in tissue sections. CONCLUSION: MSC-EVs improve graft quality by preserving the mitochondrial ultrastructure protecting the myocardium against oxidative stress, reducing apoptosis of cardiac cells and preventing the increase of pro-inflammatory cytokines.
Asunto(s)
Vesículas Extracelulares , Células Madre Mesenquimatosas , Animales , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Células Madre Mesenquimatosas/metabolismo , Femenino , Porcinos , Estrés Oxidativo , Trasplante de Corazón/métodos , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patología , Modelos Animales de Enfermedad , Miocardio/patología , Miocardio/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patologíaAsunto(s)
Daño por Reperfusión Miocárdica , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Humanos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/antagonistas & inhibidores , AnimalesRESUMEN
Vascular endothelial cell dysfunction plays an important role in myocardial ischemia-reperfusion (I/R) injury, and pannexin 1 (Panx1), an ATP-permeable channel, is closely associated with the pathophysiological processes of I/R injury. The purpose of this study was to investigate the protective effects of human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (HuMSC-EVs) and the underlying mechanism in a model of I/R injury. For the cellular model of I/R injury, human umbilical vein endothelial cells (HuVECs) were exposed to hypoxia/reoxygenation (H/R) conditions. The model cells were then treated with HuMSC-EVs, and the effects on cell survival and specific signaling activities were observed. The results showed that after H/R exposure, Panx1 expression and other markers of cellular damage were increased in HuVECs. However, treatment with HuMSC-EVs inhibited the H/R-induced increase in Panx1 expression and improved HuVEC survival. Mechanistically, HuMSC-EVs were found to inhibit the p38 mitogen-activated protein kinase (MAPK)-dependent apoptosis pathway, as evidenced by increased Bcl2 expression and reductions in p38 MAPK phosphorylation, Bax expression, and cleaved-caspase 3 expression. Together our data suggest that HuMSC-EVs alleviate H/R-induced apoptosis among HuVECs by inhibiting activity of the Panx1/p38-MAPK-dependent apoptosis pathway.
Asunto(s)
Apoptosis , Conexinas , Células Endoteliales de la Vena Umbilical Humana , Células Madre Mesenquimatosas , Proteínas del Tejido Nervioso , Proteínas Quinasas p38 Activadas por Mitógenos , Humanos , Conexinas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Células Madre Mesenquimatosas/metabolismo , Vesículas Extracelulares/metabolismo , Hipoxia de la Célula , Supervivencia Celular , Transducción de Señal , Sistema de Señalización de MAP Quinasas , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & controlRESUMEN
Myocardial infarction (MI) is a prevalent form of ischemic heart disease, significantly contributing to heart disease-related deaths worldwide. This condition is primarily caused by myocardial ischemic-reperfusion injury (MIRI). Sirtuin 5 (SIRT5) is a desuccinylase known for its ability to reduce protein succinylation. Recent studies have highlighted the potential role of SIRT5 in various human diseases, including MIRI. This study aims to investigate the specific role of SIRT5 in modulating autophagy and cardiomyocyte death in a MIRI model, as well as to identify the downstream protein targets of SIRT5. Initially, we established a hypoxia/reoxygenation (H/R)-induced MIRI cell model to measure SIRT5 expression and assess its functions. Our results indicated that H/R induction led to a downregulation of SIRT5 expression, decreased autophagy, and increased cell death. Notably, overexpression of SIRT5 effectively promoted autophagy and inhibited cell death in the MIRI cell model. Mechanistically, SIRT5 was found to directly interact with the target of myb1 membrane trafficking protein (TOM1) at the K48 site, inducing its desuccinylation and stabilization. Further rescue assays revealed that TOM1 knockdown reversed the changes in autophagy and apoptosis caused by SIRT5 overexpression in the MIRI cell model. In vivo experiments demonstrated that SIRT5 alleviated myocardial injury in MI models. In conclusion, this study uncovers the role of SIRT5-mediated desuccinylation of TOM1 in regulating autophagy-related cell death in MIRI, providing new insights into potential therapeutic strategies for MI.
Asunto(s)
Autofagia , Modelos Animales de Enfermedad , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , Transducción de Señal , Sirtuinas , Sirtuinas/metabolismo , Sirtuinas/genética , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/enzimología , Animales , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/enzimología , Infarto del Miocardio/genética , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/genética , Masculino , Ratones Endogámicos C57BL , Apoptosis , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Línea Celular , HumanosRESUMEN
OBJECTIVES: Pharmacological postconditioning can protect against myocardial ischaemia-reperfusion injury during cardiac surgery with extracorporeal circulation. The aim of this study was to observe the protective effects of fructose-1,6-bisphosphate (FDP) postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing cardiac valve replacement with extracorporeal circulation. METHODS: Patients undergoing elective mitral valve replacement and/or aortic valve replacement were divided into normal saline postconditioning group (NS group) and FDP postconditioning group (FDP group). The primary outcome was the plasma concentration of creatine kinase-MB (CK-MB). The secondary outcomes were the plasma concentrations of lactate dehydrogenase, CK, high-sensitivity C-reactive protein, alpha-hydroxybutyrate dehydrogenase and cardiac troponin I, the spontaneous cardiac rhythm recovery profile, the extracorporeal circulation time and duration of surgery, intensive care unit and postoperative hospitalization. RESULTS: Forty patients were randomly assigned to receive intervention and included in the analysis. The serum concentrations of CK-MB, lactate dehydrogenase, CK, cardiac troponin I, alpha-hydroxybutyrate dehydrogenase and high-sensitivity C-reactive protein at T1â¼4 were lower in the FDP group than in the NS group (P < 0.001). Compared with the NS group, the dosage of dopamine administered 1-90 min after cardiac resuscitation, the spontaneous cardiac rhythm recovery time and the incidence of ventricular fibrillation were lower in the FDP group (P < 0.001, P < 0.001 and P = 0.040, respectively). The values of ST- changes were increased more significantly in the NS group than in the FDP group (median [standard deviation] 1.3 [0.3] mm vs 0.7 [0.2] mm; P < 0.001). Compared with the NS group, the time of recovery of ST-segment deviations was shorter in the FDP group (50.3 [12.3] min vs 34.6 [6.9] min; P < 0.001). CONCLUSIONS: The FDP postconditioning could improve both myocardial ischaemia-reperfusion injury and the spontaneous cardiac rhythm recovery during cardiac valve surgery with extracorporeal circulation.
Asunto(s)
Implantación de Prótesis de Válvulas Cardíacas , Daño por Reperfusión Miocárdica , Humanos , Masculino , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/etiología , Femenino , Método Doble Ciego , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Persona de Mediana Edad , Fructosadifosfatos/uso terapéutico , Fructosadifosfatos/administración & dosificación , Poscondicionamiento Isquémico/métodos , Válvula Mitral/cirugía , Forma MB de la Creatina-Quinasa/sangre , Anciano , Adulto , Circulación Extracorporea/métodos , Válvula Aórtica/cirugíaRESUMEN
The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L-NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA-NONO, SIN-1) and L-NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA-NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN-1 increased tolerance to I/R injury on Day 10, but not on Day 1. L-NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L-NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.
Asunto(s)
Animales Recién Nacidos , Poscondicionamiento Isquémico , Daño por Reperfusión Miocárdica , NG-Nitroarginina Metil Éster , Óxido Nítrico , Ratas Wistar , Animales , Óxido Nítrico/metabolismo , Poscondicionamiento Isquémico/métodos , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Ratas , NG-Nitroarginina Metil Éster/farmacología , Precondicionamiento Isquémico Miocárdico/métodos , Donantes de Óxido Nítrico/farmacología , Masculino , Corazón/efectos de los fármacos , Miocardio/metabolismo , Molsidomina/farmacología , Molsidomina/análogos & derivadosRESUMEN
PURPOSE: Esaxerenone, a mineralocorticoid receptor blocker, attenuates global ischemia-induced myocardial damage and coronary endothelial dysfunction. This study aimed to determine whether esaxerenone exerted cardioprotective effects against cardioplegic arrest in Wistar rat hearts. METHODS: Isolated male Wistar rat hearts aerobically perfused via the Langendorff method for 20 min were randomly allocated to the Control (n = 6; perfused for an additional 10 min and subjected to no treatment) or Esax (n = 6; perfused with 0.1 µmol/L esaxerenone in perfusate for 10 min before ischemia) groups. Hearts in both groups were perfused with St. Thomas' Hospital No. 2 solution (STH2) for 2 min and subjected to 28 min of global ischemia. The recovery of left ventricular developed pressure (LVDP) and total troponin T leakage were measured after reperfusion. RESULTS: The final recovery of LVDP (expressed as a percentage of pre-ischemic value) in the Control and Esax groups was 50.8 ± 3.5% and 62.1 ± 5.6%, respectively (p <0.05, Esax vs. Control). The total troponin T leakage in the Control and Esax groups was 138.8 ± 18.5 ng/g heart wt and 74.3 ± 18.6 ng/g heart wt, respectively (p <0.05, Esax vs. Control). CONCLUSION: The administration of esaxerenone before cardioplegic arrest enhanced the cardioprotective effect exerted by STH2.
Asunto(s)
Modelos Animales de Enfermedad , Paro Cardíaco Inducido , Preparación de Corazón Aislado , Antagonistas de Receptores de Mineralocorticoides , Daño por Reperfusión Miocárdica , Ratas Wistar , Sulfonas , Troponina T , Función Ventricular Izquierda , Presión Ventricular , Animales , Masculino , Función Ventricular Izquierda/efectos de los fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/fisiopatología , Troponina T/sangre , Factores de Tiempo , Sulfonas/farmacología , Presión Ventricular/efectos de los fármacos , Recuperación de la Función , Miocardio/metabolismo , Miocardio/patología , Soluciones Cardiopléjicas/farmacología , PirrolesRESUMEN
AIMS: It has been reported that some peptides released by the gastro-intestinal tract play important roles in the prevention of myocardial ischemia/reperfusion injury (MIRI). Bombesin (BN) is a biologically active peptide released by non-adrenergic non-cholinergic nerves on the gastric antrum mucosa controlled by the vagus nerve. However, there is a lack of reports on the impact of BN on MIRI. This study aimed to explore the influence of BN on MIRI and its underlying mechanism. MATERIALS AND METHODS: MIRI was induced by either 30â¯min of global ischemia in Langendorff perfused rat hearts, or by ligation of the descending coronary artery for 30â¯min in anesthetized Spraque-Dawley rats, and both were followed by 120â¯min reperfusion. Infarct size and left ventricular function were assessed, and lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels were measured spectrophotometrically, while cardiomyocyte apoptosis was detected by TUNEL assay. The content of BN in plasma was measured with enzyme-linked immunosorbent assays (ELISA). The expression of caspase 3, Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were quantified. KEY FINDINGS: BN and vagus nerve stimulation improved cardiac contractile function and reduced myocardial infarct size, attenuated oxidative stress damage and myocardial cell apoptosis, increased the expression of Keap1, Nrf2, and HO-1. and these effects were blocked by using a BN receptor antagonist. SIGNIFICANCE: BN provides protection against MIRI, and its underlying mechanism is through activation of the Keap1/Nrf2/HO-1 pathway. This research provides more reliable evidence for the "gut-heart axis dialogue" and explores potential therapeutic approaches for MIRI.
Asunto(s)
Bombesina , Proteína 1 Asociada A ECH Tipo Kelch , Daño por Reperfusión Miocárdica , Factor 2 Relacionado con NF-E2 , Ratas Sprague-Dawley , Transducción de Señal , Animales , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/patología , Ratas , Transducción de Señal/efectos de los fármacos , Masculino , Bombesina/farmacología , Bombesina/análogos & derivados , Hemo Oxigenasa (Desciclizante)/metabolismo , Apoptosis/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Reperfusion after myocardial infarction (MI) can lead to myocardial ischemia/reperfusion (I/R) damage. The transcription factor (TF) broad-complex, tramtrack, and bric-a-brac (BTB) and cap'n'collar (CNC) homology 1 (BACH1) is implicated in the injury. However, the downstream mechanisms of BACH1 in affecting myocardial hypoxia/reoxygenation (H/R) damage are still fully understood. AC16 cells were stimulated with H/R conditions to model cardiomyocytes under H/R. mRNA analysis was performed by quantitative real-time PCR. Protein levels were gauged by immunoblot analysis. The effect of BACH1/cyclin-dependent kinase inhibitor 3 (CDKN3) on H/R-evoked injury was assessed by measuring cell viability via Cell Counting Kit-8 (CCK-8), apoptosis (flow cytometry and caspase 3 activity), ferroptosis via Fe2+, glutathione (GSH), reactive oxygen species (ROS) and malondialdehyde (MDA) markers and inflammation cytokines interleukin-1beta (IL-1ß) and tumor necrosis factor alpha (TNF-α). The BACH1/CDKN3 relationship was examined by chromatin immunoprecipitation (ChIP) experiment and luciferase assay. BACH1 was increased in MI serum and H/R-stimulated AC16 cardiomyocytes. Functionally, disruption of BACH1 mitigated H/R-evoked in vitro apoptosis, ferroptosis and inflammation of AC16 cardiomyocytes. Mechanistically, BACH1 activated CDKN3 transcription and enhanced CDKN3 protein expression in AC16 cardiomyocytes. Our rescue experiments validated that BACH1 disruption attenuated H/R-evoked AC16 cardiomyocyte apoptosis, ferroptosis and inflammation by downregulating CDKN3. Additionally, BACH1 disruption could activate the adenosine monophosphate-activated protein kinase (AMPK) signaling by downregulating CDKN3 in H/R-stimulated AC16 cardiomyocytes. Our study demonstrates that BACH1 activates CDKN3 transcription to induce H/R-evoked damage of AC16 cardiomyocytes partially via AMPK signaling.