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1.
Vascul Pharmacol ; 133-134: 106781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32827678

RESUMO

INTRODUCTION: Stem cell-derived cardiac myocytes are potential sources for testing cardiocytoprotective molecules against ischemia/reperfusion injury in vitro. MATERIALS AND METHODS: Here we performed a systematic analysis of two different induced pluripotent stem cell lines (iPSC 3.4 and 4.1) and an embryonic stem cell (ESC) line-derived cardiac myocytes at two different developmental stages. Cell viability in simulated ischemia/reperfusion (SI/R)-induced injury and a known cardiocytoprotective NO-donor, S-nitroso-n-acetylpenicillamine (SNAP) was tested. RESULTS: After analysis of full embryoid bodies (EBs) and cardiac marker (VCAM and cardiac troponin I) positive cells of three lines at 6 conditions (32 different conditions altogether), we found significant SI/R injury-induced cell death in both full EBs and VCAM+ cardiac cells at later stage of their differentiation. Moreover, full EBs of the iPS 4.1 cell line after oxidative stress induction by SNAP was protected at day-8 samples. CONCLUSION: We have shown that 4.1 iPS-derived cardiomyocyte line could serve as a testing platform for cardiocytoprotection.


Assuntos
Diferenciação Celular , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Células-Tronco Pluripotentes/efeitos dos fármacos , S-Nitroso-N-Acetilpenicilamina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/patologia , Troponina I/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
2.
Medicine (Baltimore) ; 99(28): e20792, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664071

RESUMO

BACKGROUND: Myocardial ischemia reperfusion injury (MIRI) is 1 of the leading causes of disability and mortality worldwide in the cardiovascular diseases. Acupuncture has been widely applied in the treatment and prevention of cardiovascular diseases in recent years. This systematic review protocol aims to provide the methods for evaluating the efficacy of Neiguan (PC6)-based acupuncture pretreatment in animal models of MIRI. METHODS AND ANALYSIS: The electronic databases of PubMed, Embase, Cochrane Library, as well as the Chinese databases such as China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, China Biology Medicine Database and WanFang Database will be searched from inception to November 2019. The outcome measures were myocardial infarct size, the level of ST-segment elevation, left ventricular ejection fraction, shortening fraction, arrhythmia score, cardiac enzymes, and cardiac troponin. Study inclusion, data extraction and quality assessment will be performed independently by 2 reviewers. RevMan 5.3 software will be used for the data synthesis and the quality of each study will be assessed independently by using the Collaborative Approach To Meta-Analysis And Review Of Animal Data From Experimental Studies checklist with minor modification. RESULTS: This review will provide a high-quality synthesis of Neiguan (PC6)-based acupuncture pretreatment for MIRI in animal models CONCLUSIONS:: This systematic review will provide conclusive evidence for whether Neiguan (PC6)-based acupuncture pretreatment is an effective intervention in animal models of MIRI. TRIAL REGISTRATION NUMBER: PROSPERO CRD42020175144.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Terapia por Acupuntura/métodos , Animais , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/terapia , China/epidemiologia , Estudos de Avaliação como Assunto , Modelos Animais , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/mortalidade , Avaliação de Resultados em Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
3.
PLoS One ; 15(7): e0235614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678819

RESUMO

Both MicroRNAs and HMGB1 took part in pathological process of myocardial I/R injury though several signaling pathways. We hypothesized that mircoRNA451 (miR-451), a group of small non-coding RNAs, could improve this injury by inhibiting HMGB1. Male SD rats were randomly distributed into 5 groups and subjected to I/R process. After 24 hours of reperfusion injury, the serum content of CK and LDH, the content of MDA in tissue and activity of SOD were detected; The infarcted areas were defined by TTC staining and Evans Blue; TUNEL staining and cleaved-Caspase 3 were used to test apoptosis; HMGB1 was detected by real-time fluorescence quantitative PCR and Western Blotting. Compared with the I/R and I/R+Ad-GFP group, upregulation of miR-451 could reduce the infarcted areas, cardiomyocytes apoptosis index, expression of cleaved-caspase 3 and content of CK and LDH significantly(P<0.05); Meanwhile, upregulation of miR-451 could also obviously inhibit HMGB1, the increase of MDA and the decrease of SOD (P<0.05). So this study revealed that upregulation of miR-451 could prevent myocardial I/R injury by suppressing HMGB1.


Assuntos
Proteína HMGB1/genética , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Regulação para Cima , Animais , Apoptose/genética , Proteína HMGB1/metabolismo , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
4.
Int Heart J ; 61(4): 806-814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728001

RESUMO

This study aimed to explore the function of miR-24 in hypoxia/reoxygenation (H/R) -induced cardiomyocyte injury.We constructed a cardiomyocyte model of H/R using the primary cardiomyocytes isolated from Sprague-Dawley rats. To explore the role of miR-24, cells were transfected with a miR-24 mimic or miR-24 inhibitor. The RNA expression levels of miR-24 and Mapk14 were determined using qRT-PCR. The proliferation and apoptosis of cells were determined using a CCK8 assay and a flow cytometer. The TargetScan website was used to predict the targets of miR-24. A dual-luciferase reporter gene assay was conducted to verify whether Mapk14 is indeed a target of miR-24. A Western blot was applied for protein detection.H/R exposure decreased the expression of miR-24 in rat cardiomyocytes. Transfection of the miR-24 mimic into cardiomyocytes reduced H/R-induced injury as evidenced by an increase in proliferation and a decrease in the apoptotic rate. By contrast, transfection of the miR-24 inhibitor aggravated H/R-induced injury. The expression of Bcl-2 was increased while the levels of Bax and Active-caspase 3 were reduced in the H/R+miR-24 mimic group compared to those in the H/R group. H/R+miR-24 inhibitor group showed the opposite results. Mapk14 was identified as a target of miR-24. The mRNA level of Mapk14 and its protein (p38 MAPK) level were negatively affected by miR-24. Furthermore, we discovered that depletion of Mapk14 reduced the promoting effect of the miR-24 inhibitor on cell apoptosis.Overall, our results illustrated that miR-24 could attenuate H/R-induced injury partly by regulating Mapk14.


Assuntos
Hipóxia/metabolismo , MicroRNAs/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Apoptose/fisiologia , Caspase 3/metabolismo , Genes Reporter/genética , Genes bcl-2/genética , Humanos , Ratos , Ratos Sprague-Dawley , Transfecção/métodos , Proteína X Associada a bcl-2/metabolismo
5.
Mol Immunol ; 125: 9-14, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32619931

RESUMO

MiR-483-3p is involved in the pathogenesis of acute myocardial infarctions, but its association with myocardial ischemia reperfusion (IR) remains mostly unknown. In this study, an in vitro model of myocardial IR injury was established by putting H9c2 cells into hypoxia reoxygenation (HR) treatment to explore the effects and possible mechanisms of miR-483-3p in myocardial IR injury. HR exposure resulted in increased miR-483-3p levels in H9c2 cells. MiR-483-3p was overexpressed or downregulated in H9c2 cells by transfection of miR-483-3p mimic or miR-483-3p inhibitor. In HR-treated H9c2 cells, MiR-483-3p mimics inhibited cell viability, promoted lactate dehydrogenase release, and increased apoptosis, but miR-483-3p inhibitors caused the opposite effects. MDM4 was verified to be the target mRNA of miR-483-3p and negatively modulated by miR-483-3p. MiR-483-3p inhibitor upregulated MDM4 and Bcl-2, but downregulated p53 and Bax in HR-treated H9c2 cells, whereas miR-483-3p overexpression produced the opposite effects.. Moreover, MDM4 siRNA transfection partially reversed the role of miR-483-3p inhibition in HR injury and p53 pathway inactivation of H9c2 cells. In summary, by targeting the MDM4/p53 pathway, miR-483-3p inhibition may alleviate myocardial HR injury. MiR-483-3p may be a potential therapeutic target of myocardial IR injury.


Assuntos
Regulação da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Técnicas In Vitro , Ratos
6.
Cardiovasc Diabetol ; 19(1): 91, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539724

RESUMO

BACKGROUND: A sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established. METHODS: The effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function. RESULTS: Dapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy. CONCLUSIONS: Acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/prevenção & controle , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
7.
Cell Prolif ; 53(6): e12818, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32468629

RESUMO

OBJECTIVES: Myocardial ischaemia/reperfusion (MI/R) injury is associated with adverse cardiovascular outcomes after acute myocardial infarction. However, the molecular mechanisms underlying MI/R injury are unclear. This study investigated the role of long non-coding RNA (lncRNA) Oip5-as1 in regulating mitochondria-mediated apoptosis during MI/R injury. MATERIALS AND METHODS: Sprague-Dawley rats were subjected to MI/R induced by ligation of the left anterior descending coronary artery followed by reperfusion. H9c2 cells were incubated under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions to mimic in vivo MI/R. RT-qPCR and Western blot were used to evaluate gene and protein levels. CCK-8 assay, biochemical assay and flow cytometric analysis were performed to assess the function of Oip5-as1. The dual-luciferase gene reporter assay and RIP assay were conducted as needed. RESULTS: Oip5-as1 expression was downregulated in the hearts of rats with MI/R and in H9c2 cells treated with OGD/R. Oip5-as1 overexpression alleviated reactive oxygen species-driven mitochondrial injury and consequently decreased apoptosis in MI/R rats and H9c2 cells exposed to OGD/R. Mechanistically, Oip5-as1 acted as a competing endogenous RNA of miR-29a and thus decreased its expression. Inhibition of miR-29a reduced the oxidative stress and cytotoxicity induced by OGD/R. Overexpression of miR-29a reversed the anti-apoptotic effect of Oip5-as1 in H9c2 cells treated with OGD/R. Further experiments identified SIRT1 as a downstream target of miR-29a. Oip5-as1 upregulated SIRT1 expression and activated the AMPK/PGC1α pathway by targeting miR-29a, thus reducing the apoptosis triggered by OGD/R. However, these effects were reversed by a selective SIRT1 inhibitor, EX527. CONCLUSIONS: Oip5-as1 suppresses miR-29a leading to activation of the SIRT1/AMPK/PGC1α pathway, which attenuates mitochondria-mediated apoptosis during MI/R injury. Our findings thus provide new insights into the molecular mechanisms of MI/R injury.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Longo não Codificante/metabolismo , Sirtuína 1/metabolismo , Animais , Apoptose , Linhagem Celular , Células Cultivadas , Potencial da Membrana Mitocondrial , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estresse Oxidativo , RNA Longo não Codificante/fisiologia , Ratos Sprague-Dawley , Transdução de Sinais
8.
Gene ; 754: 144775, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32428696

RESUMO

Myocardial ischemia/reperfusion (I/R) injury is a common consequence of restored blood supply after acute myocardial infarction (AMI), but its underlying mechanisms remain largely elusive. In this study, we aimed to investigate the functional role of long non-coding RNA PVT1 in hypoxia/reoxygenation (H/R)-treated AC16 cardiomyocytes. Our experimental results demonstrated that H/R treatment impaired the viability and increased the apoptosis of AC16 cells, and knockdown of PVT1 blocked the H/R injury. Besides, PVT1 knockdown also reduced excessive autophagy in H/R-treated AC16 cells. Furthermore, we confirmed that PVT1 might serve as a ceRNA for miR-186 in AC16 cells, and rescue experiments showed that miR-186 inhibition blocked the effects of PVT1 knockdown in H/R-treated AC16 cells. In summary, this study implied that PVT1 might be a promising therapeutic target for treating myocardial I/R injury.


Assuntos
Apoptose , Autofagia , Proteína Beclina-1/metabolismo , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , Proteína Beclina-1/genética , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Hipóxia/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Oxigênio/metabolismo , Substâncias Protetoras/metabolismo , RNA Longo não Codificante/genética
9.
Cardiovasc Drugs Ther ; 34(3): 303-310, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32236860

RESUMO

PURPOSE: The melatonin receptor (MT) agonist ramelteon has a higher affinity to MT1 than for MT2 receptors and induces cardioprotection by involvement of mitochondrial potassium channels. Activation of mitochondrial potassium channels leads to release of free radicals. We investigated whether (1) ramelteon-induced cardioprotection is MT2 receptor specific and (2) if free radicals are involved in ramelteon-induced cardioprotection. METHODS: Hearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia hearts were perfused with ramelteon (Ram) with or without the MT2 receptor inhibitor 4-phenyl-2-propionamidotetralin (4P-PDOT+Ram, 4P-PDOT). In subsequent experiments, ramelteon was administered together with the radical oxygen species (ROS) scavenger N-2-mercaptopropionylglycine (MPG+Ram). To determine whether the blockade of ramelteon-induced cardioprotection can be restored, we combined ramelteon and MPG with mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA) at different time points. Infarct size was determined by triphenyltetrazolium chloride (TTC) staining. RESULTS: Ramelteon-induced infarct size reduction was completely blocked by 4P-PDOT and MPG. Ramelteon and MPG combined with CsA before ischemia were not cardioprotective but CsA at the onset of reperfusion could restore infarct size reduction. CONCLUSIONS: This study shows for the first time that despite the higher affinity to MT1 receptors, (1) ramelteon-induced cardioprotection involves MT2 receptors, (2) cardioprotection requires ROS release, and (3) inhibition of the mPTP can restore infarct size reduction.


Assuntos
Fármacos Cardiovasculares/farmacologia , Indenos/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptor MT2 de Melatonina/agonistas , Animais , Modelos Animais de Doenças , Preparação de Coração Isolado , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Receptor MT2 de Melatonina/metabolismo , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos
10.
Microvasc Res ; 130: 104009, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333940

RESUMO

AIMS: The purpose of the present study was to investigate the possible role of TIPE2 on acute lung injury (ALI) induced by myocardial ischemia/reperfusion (MIR) in diabetic rats. METHODS: Sprague-Dawley (SD) rats were randomly separated into four groups: control+sham (C + sham); control+MIR (C + MIR); diabetes+sham (D + sham); diabetes+MIR (D + MIR). Diabetes was induced using streptozotocin. Eight weeks after diabetes induction, MIR was conducted. At 2 h after MIR, myocardial injury indices were assessed; arterial blood, bronchoalveolar lavage fluid (BALF) and lung tissues were collected for corresponding detection. RESULTS: Rats subjected to MIR showed serious ALI (estimated via pathological changes, lung injury score and Wet/Dry weight ratio), lung inflammation and pulmonary cell apoptosis compared with sham groups, especially in D + MIR group. Evaluation of protein expression in lung tissues showed that p-JNK and nuclear NF-κB p65 protein levels were higher in D + MIR group as compared with C + MIR group. Besides, either hyperglycemia or MIR can significantly upregulate TIPE2 protein levels. CONCLUSIONS: In conclusion, diabetic lungs are more susceptible to MIR. TIPE2 may involve in this pathological process, possibly through regulation of inflammation, oxidative stress and apoptosis.


Assuntos
Lesão Pulmonar Aguda/etiologia , Diabetes Mellitus Experimental/complicações , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/metabolismo , Traumatismo por Reperfusão Miocárdica/complicações , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Apoptose , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Estreptozocina , Fator de Transcrição RelA/metabolismo
11.
High Blood Press Cardiovasc Prev ; 27(3): 251-258, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32266706

RESUMO

INTRODUCTION: Ischemic heart disease is closely associated with many risk factors. Germinated brown rice extract (GBR) has potent antioxidant activities for alleviating the factors for developing heart failure such as hypertension and diabetes mellitus. AIM: The objective of the present study was to determine the cardio-protective effects of GBR and to elucidate the mechanisms underlying these effects in a model of simulated myocardial ischemic/ reperfusion injury (sI/R). METHODS: An in vitro study was performed on cultured rat cardiomyoblasts (H9c2) exposed to sI/R. The expression of apoptosis and signaling proteins was assessed using Western blot analyses. Eighteen New Zealand White rabbits were divided into 3 groups and the left circumflex coronary artery was ligated to induce myocardial ischemia. Heart functions were monitored by electrocardiography and echocardiography 0, 30, and 60 days after coronary artery ligation. RESULTS: GBR consumption group showed significantly improved cardiac function and reduced the heart rate, along with reduced mean arterial pressure and plasma glucose level. Also, GBR showed good scavenging activity, pretreatment with GBR inhibited I/R induced apoptosis by suppressing the production of caspase 3 and p38 MAPK. CONCLUSIONS: These results suggest that intake of germinated brown rice may effectively to protect cell proliferation and apoptosis and may provide important nutrients to prevent heart failure due to myocardial ischemia.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Oryza/microbiologia , Extratos Vegetais/farmacologia , Animais , Antioxidantes/isolamento & purificação , Caspase 3/metabolismo , Linhagem Celular , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fermentação , Hemodinâmica/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Coelhos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Nutr Metab Cardiovasc Dis ; 30(5): 829-842, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32278611

RESUMO

BACKGROUND AND AIM: The transcription factor GATA-4 plays an important role in myocardial protection. Astragaloside IV (Ast-IV) was reported with the effects on improving cardiac function after ischemia. In this study, we explored how Ast-IV interacts with GATA-4 to protect myocardial cells H9c2 against Hypoxia/Reoxygenation (H/R) stress. METHODS AND RESULTS: H9c2 cells were cultured under the H/R condition. Various cell activity and morphology assays were used to assess the rates of apoptosis and autophagy. In these H/R injured H9c2 cells, increased apoptosis (P < 0.01) and autophagosome number (P < 0.01) were observed, and the addition of Ast-IV ameliorated this tendency. Mechanistically, we used the RT-qPCR and Western blot to evaluate the expressions of various molecules. The results showed that Ast-IV treatment upregulated gene expression of GATA-4 (P < 0.01) and the survival factors (Bcl-2, P < 0.05; p62, P < 0.01), but suppressed apoptosis and autophagy related genes (PARP, Caspase-3, Beclin-1, and LC3-II; All P < 0.01). Furthermore, overexpressing of GATA-4 by its agonist phenylephrine can also protect H/R injured H9c2 cells, and the addition of Ast-IV further enhanced this protection of GATA-4. In contrast, silencing GATA-4 expression abolished the H/R protection of Ast-IV, which demonstrated that the myocardial protection of Ast-IV is mediated by GATA-4. Lastly, along with GATA overexpression, enhanced interactions between Bcl-2 and Beclin-1 were detected by Chromatin immunoprecipitation (P < 0.01). CONCLUSION: Ast-IV rescued the H/R injury induced apoptosis and autophagy in H9c2 cells. Ast-IV treatment can stimulate the overexpression of GATA-4, and further enhanced the myocardial protection effect of GATA-4.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fator de Transcrição GATA4/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Hipóxia Celular , Linhagem Celular , Citoproteção , Fator de Transcrição GATA4/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Transdução de Sinais , Regulação para Cima
13.
Biochem Biophys Res Commun ; 525(3): 759-766, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32145915

RESUMO

Formononetin (FN), a methoxy isoflavone abundant in many plants and herbs, has been evidently proven to possess multiple medicinal properties. Our study aimed to clarify the impact of FN on myocardial ischemia/reperfusion (I/R) injury (MIRI) and the involved mechanism. A rat model of MIRI was produced by ligation and loosening of the left anterior descending (LAD) branch of the coronary artery. Rats received 10 and 30 mg/kg of FN when the reperfusion started. At 24 h after surgery, cardiac function, infarct size, and sera levels of the cardiac markers and inflammatory mediators were measured. To mimic the inflammasome activation in cardiomyocytes, neonatal rat cardiomyocytes (NRCMs) were cultured and treated with lipopolysaccharide (LPS) plus nigericin. Cell death and reactive oxygen species (ROS) were determined. Myocardial expression and activation of the nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome in rats were examined by western blotting. The level of thioredoxin interacting protein (TXNIP)-NLRP3 interaction was assessed. FN notably attenuated cardiac dysfunction, infarct size, release of cardiac markers, and elevation of TNF-α, IL-1ß, and IL-6. FN alleviated LPS plus nigericin-induced injury and ROS increase in NRCMs. Western blotting revealed that FN suppressed the activation of NLRP3 inflammasome and TXNIP-NLRP3 interaction in rats. These findings indicate that FN ameliorated MIRI in rats and inhibited the activation of the NLRP3 inflammasome, at least partially, attributable to suppression of the ROS-TXNIP-NLRP3 pathway.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Isoflavonas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Testes de Função Cardíaca , Inflamassomos/metabolismo , Inflamação/patologia , Isoflavonas/química , Isoflavonas/farmacologia , Lipopolissacarídeos , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Nigericina , Ligação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
14.
Mol Cell Biochem ; 468(1-2): 47-58, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32162053

RESUMO

Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and reduce cardiac dysfunction following ischemia/reperfusion (I/R) injury in C57BL/6NCrl-Leprdb-lb/Crl mice with MetS phenotypes. Adult male MetS mice were randomized to receive vehicle solvent or tadalafil (1 mg/kg,i.p.) daily for 28 days and C57BL/6NCrl mice served as healthy wild-type controls. After 28 days, cardiac function was assessed by echocardiography and hearts from a subset of mice were isolated and subjected to 30 min of global ischemia followed by 60 min of reperfusion (I/R) in ex vivo Langendorff mode. Body weight, blood lipids, and glucose levels were elevated in MetS mice as compared with wild-type controls. The dyslipidemia in MetS was ameliorated following tadalafil treatment. Although left ventricular (LV) systolic function was minimally altered in the MetS mice, there was a significant diastolic dysfunction as indicated by reduction in the ratio of peak velocity of early to late filling of the mitral inflow, which was significantly improved by tadalafil treatment. Post-ischemic cardiac function, heart rate, and coronary flow decreased significantly in MetS mice compared to wild-type controls, but preserved by tadalafil treatment. Myocardial infarct size was significantly smaller following I/R, which was associated with higher plasma levels of nitrate and nitrite in the tadalafil-treated MetS mice. In conclusion, tadalafil induces significant cardioprotective effects as shown by improvement of LV diastolic function, lipid profile, and reduced infarct size following I/R. Tadalafil treatment enhanced NO production, which may have contributed to the cardioprotective effects.


Assuntos
Síndrome Metabólica/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Cardiotônicos/farmacologia , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Coração/efeitos dos fármacos , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Nitratos/sangue , Nitritos/sangue
15.
Int Heart J ; 61(2): 347-354, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32132320

RESUMO

Myocardial infarction (MI) is one of the major causes of death worldwide, and the therapeutic strategies of MI are still limited. In this study, we investigated the function of miR-665 in MI. In the present study, an ischemia/reperfusion (I/R) rat model and a hypoxia/reoxygenation (H/R)-induced H9c2 cell model were successfully established to mimic the MI for in vivo and in vitro studies. The concentrations of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), tumor necrosis factor alpha (TNF-α), IL-6, and reactive oxygen species (ROS) were then measured. Moreover, cell viability and apoptosis were detected by MTT assay, TdT-mediated dUTP nick end labeling (TUNEL), and PI/FITC-annexin V assay. The binding of miR-665 and Pak1 was determined by luciferase assay. miR-665 was upregulated in I/R rats, and the overexpression of miR-665 significantly increased LDH, CK-MB, TNF-α, IL-6, and ROS concentrations and induced cell apoptosis, while knockdown of miR-665 had opposite results. Consistent with in vivo results, miR-665 induced cell apoptosis and ROS generation in H/R-treated H9c2 cells. More importantly, Pak1 was the target gene of miR-665, and knockdown of miR-665 depressed the accumulation of ROS and cell apoptosis by targeting Pak1 and promoting the phosphorylation of Akt, whereas knockdown of Pak1 could attenuate the protection of miR-665 inhibitor in H/R-treated H9c2 cells. Therefore, knockdown of miR-665 protects against cardiomyocyte ischemia/reperfusion injury-induced ROS accumulation and apoptosis through activating Pak1/Akt signaling in MI. In general, understanding the biology and modulation of miR-665 may have the potential to counteract the development of MI.


Assuntos
MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Apoptose , Linhagem Celular , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Masculino , MicroRNAs/genética , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Quinases Ativadas por p21/genética
16.
Acta Cir Bras ; 35(1): e202000107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215448

RESUMO

PURPOSE: Patients with diabetes are vulnerable to myocardial I/R (ischaemia/reperfusion) injury, but are not responsive to IPO (ischaemic post-conditioning). We hypothesized that decreased cardiac Adiponectin (APN) is responsible for the loss of diabetic heart sensitivity to IPO cardioprotecton. METHODS: Diabetic rats were subjected to I/R injury (30 min of LAD occlusion followed by 120 min of reperfusion). Myocardial infarct area was determined by TTC staining. Cardiac function was monitored by a microcatheter. ANP, 15-F2t-isoprostane, nitrotyrosine and MDA were measured by assay kits. Levels of p-Akt, total-Akt and GAPDH were determined by Western Blot. RESULTS: Diabetic rats subjected to myocardial IR exhibited severe myocardial infarction and oxidative stress injury, lower APN in the plasma and cardiac p-Akt expression ( P <0.05). IPO significantly attenuated myocardial injury and up-regulated plasma APN content and cardiac p-Akt expression in non-diabetic rats but not in diabetic rats. Linear correlation analysis showed that the expression of adiponectin was positively correlated with p-Akt and negatively correlated with myocardial infarction area ( P <0.01). CONCLUSION: Protective effect of IPO was tightly correlated with the expression of adiponectin, exacerbation of I/R injury and ineffectiveness of IPO was partially due to the decline of adiponectin and inactivation of Akt in diabetes mellitus.


Assuntos
Adiponectina/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Pós-Condicionamento Isquêmico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Glicemia/análise , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Acta Cir Bras ; 35(1): e202000105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215465

RESUMO

PURPOSE: To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC). METHODS: The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß and c-Jun N-terminal kinase (JNK) were assessed. RESULTS: Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1ß, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA. CONCLUSION: HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.


Assuntos
Benzoquinonas/farmacologia , Proteínas do Sistema Complemento/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lactamas Macrocíclicas/farmacologia , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Creatina Quinase Forma MB/metabolismo , Mediadores da Inflamação , Pós-Condicionamento Isquêmico/métodos , Masculino , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
18.
Circ J ; 84(4): 626-635, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32161201

RESUMO

BACKGROUND: Macrophages play an important role in the development of cardiac fibrosis. However, the roles of different macrophage subtypes in cardiac fibroblast (CF) activation and cardiac fibrosis are unknown.Methods and Results:Bone marrow-derived macrophages (BMDMs) were treated with different stimuli to induce differentiation into M1, M2a, M2b, and M2c macrophage subtypes. CFs were co-cultured with different subtypes of macrophages or cultured with macrophage supernatants. Results revealed that M2b macrophages significantly suppressed the proliferation and migration of CFs, the expression of fibrosis-related proteins (collagen I [COL-1] and α-smooth muscle actin [α-SMA]), and differentiation into cardiac myofibroblasts (MFs). The opposite effects were observed with M2a macrophages. A rat model of cardiac ischemia/reperfusion (I/R) injury was used to determine the effect of M2b macrophages transplantation. After cardiac I/R injury, transplantation of M2b macrophages improved cardiac function and reduced cardiac fibrosis. The effect of macrophage subtypes on p-ERK, ERK, p-p38, and p38 phosphorylation was examined by Western blotting. The results showed that M2b macrophages significantly inhibited the mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSIONS: These study results demonstrate for the first time that different subtypes of macrophages have different roles in regulating CF activation. M2b macrophages inhibit CF activation, and thus can be considered anti-fibrotic macrophages. M2a macrophages promote CF activation, and thus are pro-fibrotic macrophages.


Assuntos
Comunicação Celular , Diferenciação Celular , Fibroblastos/metabolismo , Macrófagos/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Actinas/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/patologia , Fibrose , Macrófagos/patologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Fenótipo , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Circ J ; 84(4): 616-625, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32115441

RESUMO

BACKGROUND: Ischemic postconditioning (IPostC) is an endogenous protective mechanism to reduce ischemia-reperfusion (I/R) injury. However, whether IPostC protects aged cardiomyocytes against I/R injury is not fully understood. Considering the protective function of microRNA 30a (miR-30a) against ischemia-induced injury in H9C2 cells, its role in the protective effects of IPostC on I/R injury of aged cardiomyocytes was investigated further.Methods and Results:To mimic I/R and IPostC in vitro, the aged cardiomyocyte model for hypoxia postconditioning (HPostC) treatment was established by 9 days of incubation with 8 mg/mL D-galactose and then followed by exposure to hypoxic environment. HPostC significantly alleviated hypoxia/reoxygenation (H/R) injury and reduced autophagy of aged cardiomyocytes, as evidenced by decreased LC3B-II expression and increased p62 by Western blot. Quantified by quantitative real-time polymerase chain reaction (qRT-PCR), miR-30a was increased in aged cardiomyocytes treated with HPostC compared with I/R injury group. Overexpression of miR-30a by LV3-rno-miR-30a mimic promoted cardioprotective effect of HPostC in aged cardiomyocytes by suppressing BECN1-mediated autophagy, all of which was abrogated by knockdown of miR-30a expression. Epigenetic analyses demonstrated that HPostC reduced DNA methyltransferase 3b-mediated DNA hypomethylation levels at miR-30a promoter, leading to upregulation of miR-30a. CONCLUSIONS: HPostC protected aged cardiomyocytes survival against H/R injury via DNMT3b-dependent activation of miR-30a. miR-30a could be a potential therapeutic target for ischemic myocardial infarction.


Assuntos
Autofagia , Senescência Celular , Metilação de DNA , Epigênese Genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Hipóxia Celular , Linhagem Celular , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Regiões Promotoras Genéticas , Ratos , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais
20.
Int J Mol Sci ; 21(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098266

RESUMO

An increased incidence of myocardial infarction (MI) has recently emerged as the cause of cardiovascular morbidity and mortality worldwide. In this study, cardiac function was investigated in a rat myocardial ischemia/reperfusion (I/R) model using echocardiography. Metformin administration significantly increased ejection fraction and fractional shortening values on Days 3 and 7 when MI occurred, indicating that metformin improved left ventricular systolic function. In the Sham + MET and MI + MET groups, the E' value was significantly different up to Day 3 but not at Day 7. This may mean that left ventricular diastolic function was effectively restored to some extent by Day 7 when metformin was administered. These results suggest that diastolic dysfunction, assessed by echocardiography, does not recover in the early phase of ischemic reperfusion injury in the rat myocardial I/R model. However, administering metformin resulted in recovery in the early phase of ischemic reperfusion injury in this model. Further gene expression profiling of left ventricle tissues revealed that the metformin-treated group had notably attenuated immune and inflammatory profiles. To sum up, a rat myocardial I/R injury model and ultrasound-based assessment of left ventricular systolic and diastolic function can be used in translational research and for the development of new heart failure-related drugs, in addition to evaluating the potential of metformin to improve left ventricular (LV) diastolic function.


Assuntos
Ecocardiografia , Regulação da Expressão Gênica/efeitos dos fármacos , Metformina/farmacologia , Traumatismo por Reperfusão Miocárdica , Disfunção Ventricular Esquerda , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/metabolismo
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