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1.
Cardiovasc Ther ; 2020: 1389312, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32788926

RESUMO

Inflammation plays a major role in the development of myocardial ischemia-reperfusion (IR) injury. Recombinant human brain natriuretic peptide (rhBNP), a man-made version of a peptide that is elevated in heart failure, exhibits anti-inflammatory effects in various tissues. However, its role in myocardial IR injury remains unclear. In this study, we demonstrate that treatment with rhBNP provided protection for mice against myocardial IR injury as manifested by reduced infarct size and well-preserved myocardial, attenuated inflammatory infiltration and CD4+ T cell proliferation function, and inhibited expression of proinflammatory related genes. Furthermore, mechanistic studies revealed that rhBNP inhibited Jurkat T proliferation by promoting PI3K/AKT/mTOR phosphorylation. Collectively, our data suggest that the administration of rhBNP during IR injury could expand our understanding of the cardioprotective effects of rhBNP.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Peptídeo Natriurético Encefálico/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Células Jurkat , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/patologia , Fosforilação , Proteínas Recombinantes/farmacologia , Transdução de Sinais
2.
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
3.
Life Sci ; 257: 118004, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621918

RESUMO

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI. OBJECTIVES: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection. METHOD: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test. RESULTS: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress. CONCLUSIONS: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.


Assuntos
Dexmedetomidina/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/prevenção & controle , Idoso , Animais , Apoptose/efeitos dos fármacos , China , Dexmedetomidina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Isquemia/metabolismo , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo , Reperfusão Miocárdica/métodos , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estudos Prospectivos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Nat Commun ; 11(1): 3273, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32601301

RESUMO

Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.


Assuntos
Ferro/análise , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Idoso , Animais , Estudos Transversais , Feminino , Ferritinas/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Cicatrização
5.
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
6.
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
7.
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
8.
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
9.
Nat Commun ; 11(1): 1315, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161256

RESUMO

Myocardial ischemia is one of the leading health problems worldwide. Therapy consists of the restitution of coronary perfusion which is followed by myocardial inflammation. Platelet-neutrophil interaction is a crucial process during inflammation, yet its consequences are not fully understood. Here, we show that platelet-neutrophil complexes (PNCs) are increased in patients with acute myocardial infarction and that this is associated with increased levels of neuronal guidance protein semaphorin 7A (SEMA7A). To investigate this further, we injected WT animals with Sema7a and found increased infarct size with increased numbers of PNCs. Experiments in genetically modified animals identify Sema7a on red blood cells to be crucial for this condition. Further studies revealed that Sema7a interacts with the platelet receptor glycoprotein Ib (GPIb). Treatment with anti-Sema7a antibody protected from myocardial tissue injury. In summary, we show that Sema7a binds to platelet GPIb and enhances platelet thrombo-inflammatory activity, aggravating post-ischemic myocardial tissue injury.


Assuntos
Antígenos CD/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Semaforinas/metabolismo , Trombose/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Plaquetas/imunologia , Plaquetas/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Eritrócitos/imunologia , Eritrócitos/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/imunologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/imunologia , Miocárdio/patologia , Estudos Prospectivos , Semaforinas/genética , Semaforinas/imunologia , Trombose/imunologia , Adulto Jovem
10.
Mol Cell Biochem ; 466(1-2): 129-137, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32056105

RESUMO

This study evaluated the cardioprotective effects of a miR-1275 mimic in a rat model of myocardial ischemia-reperfusion (I/R)-induced myocardial injury (MI). Three groups of rats were established: a sham-operated group, a MI group and a MI+miR-1275 group pretreated for 1 week i.p. with a miR-1275 mimic at a concentration of 30 pmol/mL. MI was induced by I/R. The levels of myocardial enzymes in serum were estimated in all rats, together with haemodynamic functions. The effects of the miR-1275 mimic were determined based on the serum concentrations of inflammatory mediators in the treated vs. sham and MI rats. In addition, western blot assay and immunohistochemical analyses were performed to examine the effect of the miR-1275 mimic on the Wnt/NF-kB signalling pathway in MI rats. Treatment with the miR-1275 mimic attenuated the altered levels of myocardial enzymes and haemodynamic functions seen in MI rats. The myocardial infarct was smaller in rats treated with the miR-1275 mimic than in MI rats. The miR-1275 mimic also reduced myocardiocyte apoptosis and ameliorated the altered Wnt/KF-kB pathway. These results demonstrate the efficacy of the miR-1275 mimic in preventing myocardial I/R-induced MI in rats, by regulating the Wnt/NF-κB pathway.


Assuntos
Apoptose/efeitos dos fármacos , Materiais Biomiméticos/farmacologia , MicroRNAs/farmacologia , Miocárdio/metabolismo , NF-kappa B/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
11.
Transplantation ; 104(9): 1869-1878, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32058468

RESUMO

BACKGROUND: Triple progressive thermopreconditioning (3PTP) may induce high Hsp-70 expression to maintain cardiac function. We suggest that 3PTP may reduce myocardial ischemia/reperfusion (I/R) injury during organ transplantation through Bag3/Hsp-70 mediated defense mechanisms. METHODS: Male Wistar rats were divided into sham control group and 72 h after 3PTP in a 42°C water bath (3PTP) group. Rats underwent 60 min of ischemia by occlusion of the left anterior descending coronary artery followed by 240 min reperfusion. Hemodynamic parameters, including the electrocardiogram, microcirculation, heart rate, left ventricular end-diastolic pressure, maximal rate of rise (+dp/dt), and fall (-dp/dt) in the left ventricular pressure for index of contraction and relaxation were determined. Myocardial infarct size was evaluated by the Evans blue-2,3,5-triphenyltetrazolium chloride method. 3PTP-induced protective mechanisms were determined by Western blot and immunohistochemistry. RESULTS: Cardiac I/R depressed cardiac microcirculation, induced S-T segment elevation, and R-R and P-R interval elongation increased infarct size associated with erythrocyte extravasation, leukocytes and macrophage/monocyte infiltration, granulocyte colony-stimulating factor, poly(ADP-ribose) polymerase 1 stain, and transferase-mediated dUTP-biotin nick end labeling positive cells. However, 3PTP evoked significant cardioprotection against I/R injury, characterized by the increased +dp/dt value and the decreased elevated left ventricular end-diastolic pressure, erythrocyte extravasation, leukocyte and macrophage/monocyte infiltration, granulocyte colony-stimulating factor expression, poly(ADP-ribose) polymerase 1 expression, transferase-mediated dUTP-biotin nick end labeling positive cells, and fragmentation and infarct area. In addition, 3PTP increased Hsp-70 and Bag3 expression and decreased Bax/Bcl-2 ratio, but did not affect the Beclin-1 and LC3-II/LC3-I ratio in the heart with I/R injury. CONCLUSIONS: 3PTP therapies may through Bag3 upregulation alleviate I/R injury-induced left ventricular structural deterioration and dysfunction.


Assuntos
Ventrículos do Coração/patologia , Precondicionamento Isquêmico Miocárdico , Contração Miocárdica/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/fisiologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Masculino , Microcirculação , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Ratos , Ratos Wistar
12.
Respir Med ; 161: 105852, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056726

RESUMO

OBJECTIVE: The aim of the study was to investigate the mechanism and effect of FBXL10 in myocardial ischemia reperfusion injury in vivo and in vitro. METHODS: The myocardial ischemia reperfusion (I/R) model was established by 30 min of coronary occlusion followed by 2 h of reperfusion in rats. Western blot and TUNEL assay were used to measure the apoptosis during I/R. The expression levels of endoplasmic reticulum related proteins in myocardial tissues and H9c2 cells were detected by immunohistochemistry staining and immunofluorescence staining. Flow cytometry and CCK-8 were used to detect the apoptosis and viability of H9c2 cells. RESULTS: The results revealed that FBXL10 significantly reduced myocardial infarction, improved the pathological morphology of myocardium, markedly reduced inflammatory response in the myocardial ischemia reperfusion rats. Moreover the expressions of endoplasmic reticulum stress key proteins were caused by I/R were suppressed significantly by FBXL10 treatment, including CHOP, GRP78, ATF4 and p-PERK. Additionally FBXL10 inhibited the expression of endoplasmic reticulum stress key proteins in H/R H9c2 cells. Furthermore, FBXL10 reduced the levels of apoptotic cells and inflammatory response compared with I/R and H/R group. CONCLUSION: Taken together, we found that FBXL10 could attenuate I/R injury through inhibiting endoplasmic reticulum stress (ERs).


Assuntos
Estresse do Retículo Endoplasmático/genética , Proteínas F-Box/fisiologia , Histona Desmetilases com o Domínio Jumonji/fisiologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Apoptose/genética , Células Cultivadas , Expressão Gênica/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
13.
Environ Toxicol ; 35(7): 774-782, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32061153

RESUMO

This study aims to investigate the protective effects of the Bauhinia championii (BC) against ischemia/reperfusion (I/R)-induced injury in an isolated heart model. Langendorff-perfused C57BL/6JNarl mice hearts were performed with 30 minutes ischemia and 60 minutes reperfusion by left anterior descending artery ligation. Before reperfusion, boiling water extracts of BC (10 mg/L) was pretreated for 15 minutes. During reperfusion, BC significantly decreased the occurrence of ventricular arrhythmias by lead II electrocardiogram (ECG). Electrophysiological effect of BC was further determined in isolated ventricular myocytes by whole-cell patch clamp technique. The underlying mechanism may result from its Na+ channel blocking activity characterized with reduced rise slope of action potential and Na+ current density. Moreover, BC dramatically reduced I/R-caused infarct size, which was accessed by 2,3,5-triphenyltetrazolium chloride (TTC) assay. Since BC decreased I/R-induced myoglobin release and oxidation of Ca2+ -calmodulin-dependent protein kinase, inhibition of myocardial necroptosis may account for the protective effects of BC on myocytes lose. This study indicated that BC may prevent I/R induced ventricular arrhythmias and myocyte death by blocking Na+ channels and decreasing necroptosis, respectively. Since most of the available antiarrhythmic remedies have unwanted adverse actions, BC could be a novel candidate for the treatment of myocardial infarction and ventricular arrhythmia.


Assuntos
Bauhinia/química , Coração/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Extratos Vegetais/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Eletrocardiografia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Necroptose/efeitos dos fármacos , Técnicas de Patch-Clamp , Componentes Aéreos da Planta/química , Extratos Vegetais/isolamento & purificação , Bloqueadores dos Canais de Sódio/isolamento & purificação , Canais de Sódio/metabolismo
14.
Acta Cir Bras ; 34(11): e201901106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31939595

RESUMO

PURPOSE: To investigate whether GDF11 ameliorates myocardial ischemia reperfusion (MIR) injury in diabetic rats and explore the underlying mechanisms. METHODS: Diabetic and non-diabetic rats subjected to MIR (30 min of coronary artery occlusion followed by 120 min of reperfusion) with/without GDF11 pretreatment. Cardiac function, myocardial infarct size, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), superoxide dismutase (SOD) 15-F2tisoprostane, autophagosome, LC3II/I ratio and Belcin-1 level were determined to reflect myocardial injury, oxidative stress and autophagy, respectively. In in vitro study, H9c2 cells cultured in high glucose (HG, 30mM) suffered hypoxia reoxygenation (HR) with/without GDF11, hydrogen peroxide (H2O2) and autophagy inhibitor 3-methyladenine (3-MA) treatment, cell injury; oxidative stress and autophagy were assessed. RESULTS: Pretreatment with GDF11 significantly improved cardiac morphology and function in diabetes, concomitant with decreased arrhythmia severity, infarct size, CK-MB, LDH and 15-F2tisoprostane release, increased SOD activity and autophagy level. In addition, GDF11 notably reduced HR injury in H9c2 cells with HG exposure, accompanied by oxidative stress reduction and autophagy up-regulation. However, those effects were completely reversed by H2O2 and 3-MA. CONCLUSION: GDF11 can provide protection against MIR injury in diabetic rats, and is implicated in antioxidant stress and autophagy up-regulation.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Western Blotting , Cardiotônicos/farmacologia , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Hemodinâmica/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Traumatismo por Reperfusão Miocárdica/patologia , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Estreptozocina , Superóxido Dismutase/análise , Regulação para Cima/efeitos dos fármacos
15.
Gene ; 731: 144324, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31904498

RESUMO

BACKGROUND/AIMS: lncRNA NEAT1 is involved in the development of many diseases. However, the function of lncRNA NEAT1 in myocardial infarction is unclear. Therefore, this experimental design based on lncRNA NEAT1 to explore the pathogenesis of myocardial infarction. METHODS: RT-qPCR was used to detect the expression of lncRNA NEAT1 and miR-378a-3p in peripheral blood and mouse cardiomyocytes of patients with myocardial infarction. MTT assay, flow cytometry, Caspase-3 kit and transwell assay were used to detect the effects of lncRNA NEAT1 and miR-378a-3p on cardiomyocyte proliferation, apoptosis and migration. Target gene prediction and screening, luciferase reporter assays were used to verify downstream target genes for lncRNA NEAT1 and miR-378a-3p. Western blotting was used to detect the protein expression of Atg12 and related autophagy genes. RESULTS: lncRNA NEAT1 was highly expressed in peripheral blood and mouse cardiomyocytes of patients with myocardial infarction. Moreover, lncRNA NEAT1 significantly promoted cell proliferation and migration of cardiomyocytes. In addition, lncRNA NEAT1 inhibited miR-378a-3p expression, and miR-378a-3p inhibited Atg12 expression, while lncRNA NEAT1 regulated expression of Atg12 and related autophagic factors via miR-378a-3p. Knockout of microRNA-378-3p reversed the effects of NEAT1 silencing on cell damage. CONCLUSION: lncRNA NEAT1 can regulate the proliferation of cardiomyocytes by regulating miR-378-3p/Atg12 axis, thus accelerating the occurrence and development of cardiomyocytes.


Assuntos
MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , Angina Instável/genética , Angina Instável/patologia , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo/genética , Regulação da Expressão Gênica , Inativação Gênica/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/patologia , Ratos , Estudos Retrospectivos
16.
Cardiovasc Eng Technol ; 11(2): 219-227, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31916040

RESUMO

PURPOSE: Recent studies have demonstrated that miRNAs play a vital role in regulating myocardial ischemia/reperfusion injury (MIRI). MiR-217 has been proven to be implicated in cardiac diseases such as chronic heart failure and cardiac myxoma. However, the role of miR-217 in MIRI is not clear. METHODS: A mouse MIRI model was established and the myocardial infarct size was evaluated by TTC staining. The expression level of miR-217 in I/R group was determined by real-time polymerase chain reaction. Subsequently, MIRI mice and H9C2 cells were administrated with miR-217 inhibitor in vivo and in vitro, respectively. The levels of TNF-α and IL-6 were measured by commercially available ELISA kits. Blood and cell samples were collected for the measurement of lactate dehydrogenase (LDH) level and caspase-3 activity. Cell viability was assessed with the CCK-8 assay. We then explored the detailed molecular mechanisms by TargetScan 7.1 database and further studies were performed to prove the prediction by dual-luciferase reporter assay. RESULTS: Larger stainless infarct areas were observed in the MIRI group, accompanied by inceased serum LDH activity, indicating the mouse MIRI model was successfully established. MiR-217 was up-regulated in MIRI mice and hypoxia/reoxygenation-treated H9C2 cells. MiR-217 knockdown alleviated the MIRI in MIRI mouse model, and also attenuated the myocardial hypoxia/reoxygenation injury in H9C2 cells. Moreover, dual specificity protein phosphatase 14 (DUSP14) was proved to be a target of miR-217. Besides, further study indicated that inhibition of miR-217 protected against MIRI through inactivating NF-κB and MAPK pathways via targeting DUSP14. CONCLUSIONS: MiR-217 inhibition protected against MIRI through inactivating NF-κB and MAPK pathways by targeting DUSP14. This study may provide valuable diagnostic and factors and therapeutic agents for MIRI.


Assuntos
Antagomirs/administração & dosagem , Técnicas de Silenciamento de Genes , MicroRNAs/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/enzimologia , NF-kappa B/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Fosforilação , Transdução de Sinais
17.
Mol Med Rep ; 21(3): 1011-1020, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922242

RESUMO

Increasing evidence has indicated that miR­155 is closely associated with apoptosis, which may protect the myocardium and diminish the infarct area in myocardial ischemia reperfusion injury (IRI). In addition, studies have revealed that miR­155 serves a leading role in promoting fibroblast inflammation, cardiac dysfunction and other aspects of myocardial injury. The present study aimed to uncover the function and potential biological mechanism of miR­155 in myocardial IRI. The rat H9c2 myocardial cells was treated with hypoxia/reoxygenation (H/R) to simulate IRI in vitro. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to detect the expression levels of miR­155 mRNA. Cell Counting Kit­8 and flow cytometry assays and western blot analysis were applied to determine the biological behaviors of the H/R­treated cells. The association between miR­155 and BAG family molecular chaperone regulator 5 (BAG5) was predicted by bioinformatics software and was confirmed by dual luciferase assay. RT­qPCR and western blot analysis were used to analyze the expression of BAG5. The key proteins involved in mitogen­activated protein kinase (MAPK)/JNK signaling pathway were detected by western blot analysis. The data from the RT­qPCR assay indicated that the expression of miR­155 was markedly upregulated in the H/R model, and that downregulation of miR­155 may promote cell proliferation and inhibit cell apoptosis, and vice versa. BAG5, which was downregulated in the H/R model, was confirmed as a target of miR­155 and negatively modulated by miR­155. The key proteins involved in MAPK/JNK signaling, which were highly expressed in the H/R model, were suppressed by treatment with the miR­155 inhibitor, and overexpression of BAG5 promoted the protective effect of miR­155 inhibition on cell injury caused by H/R. In addition, the expression patterns of hypoxia­inducible factor 1­α and von Hippel­Lindau were altered following different treatments. Taken together, the data from the present study indicated that miR­155 inhibition represented a potential treatment strategy to improve myocardial H/R injury, which may be associated with targeting BAG5 and inhibition of the MAPK/JNK pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Hipóxia Celular , Linhagem Celular , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Ratos
18.
Artif Cells Nanomed Biotechnol ; 48(1): 345-352, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899964

RESUMO

Prokineticin 2 (PK2) was reported to be decreased in the hearts of end-state heart failure patients. Our study aimed to explore the effects of PK2 on hypoxia/reoxygenation (H/R) injury and the underlying mechanism. H9c2 cardiomyocytes were treated with 5 nM PK2 in the presence or absence of 5 mM dual phosphatidylinositol 3-kinase (PI3K)/the mammalian target of rapamycin (mTOR) inhibitor (BEZ235) for 24 h and then subjected to H/R treatment. Cell viability and lactate dehydrogenase (LDH) release were evaluated by CCK-8 and LDH release assays, respectively. Apoptosis was determined by flow cytometry analysis. Oxidative stress was assessed by measuring superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) content. Results showed that H/R treatment decreased PK2 expression and inactivated the Akt/mTOR pathway in H9c2 cardiomyocytes. PK2 treatment activated the Akt/mTOR pathway in H/R-exposed H9c2 cardiomyocytes. H/R stimulation suppressed cell viability, increased LDH release, induced apoptosis and oxidative stress in H9c2 cardiomyocytes, while these effects were neutralised by treatment with PK2. However, the inhibitory effects of PK2 on H/R-induced injury in H9c2 cardiomyocytes were abolished by the addition of BEZ235. In conclusion, PK2 relieved H/R-induced injury in H9c2 cardiomyocytes by activation of the Akt/mTOR pathway.


Assuntos
Hormônios Gastrointestinais/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Neuropeptídeos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular , Hormônios Gastrointestinais/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Neuropeptídeos/genética , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Serina-Treonina Quinases TOR/genética
19.
Cardiovasc Pathol ; 46: 107180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945680

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are under consideration for myocardial ischemia-reperfusion (I/R) injury therapy, but their mechanism remains to be evaluated. In this article, we aimed to study the effects of the miR-29a/follistatin-like 1 axis in bone marrow-derived mesenchymal stem cells on modulating myocyte apoptosis after hypoxia-reoxygenation (H/R) injury. METHODS: An in vitro myocardial ischemia-reperfusion injury model of H9c2 cells was developed by hypoxia-reoxygenation injury. The mRNA levels of follistatin-like 1, Bcl-2, Bax, and miR-29a and the protein levels of Bcl-2, Bax, cleaved caspase-3, and components of the JAK2/STAT3 pathway were detected by qRT-PCR and western blotting, respectively. Secretion of follistatin-like 1 was evaluated by enzyme-linked immunosorbent assay. Cell apoptosis was evaluated by flow cytometry. The interaction between miR-29a and follistatin-like 1 was evaluated by dual luciferase reporter assay. RESULTS: MiR-29a suppressed the expression and secretion of follistatin-like 1 in bone marrow-derived mesenchymal stem cells. Overexpression of follistatin-like 1 in bone marrow-derived mesenchymal stem cells decreased apoptosis of myocytes induced by hypoxia-reoxygenation. Cell apoptosis in myocytes was promoted by conditioned medium from bone marrow-derived mesenchymal stem cells with ectopic miR-29a expression. Conditioned medium of miR-29a-overexpressing bone marrow-derived mesenchymal stem cells inhibited the JAK2/STAT3 pathway in myocytes to promote apoptosis of myocytes. CONCLUSIONS: MiR-29a in bone marrow-derived mesenchymal stem cells inhibits follistatin-like 1 secretion and promotes myocyte apoptosis by suppressing the JAK2/STAT3 pathway in hypoxia-reoxygenation injury.


Assuntos
Apoptose , Proteínas Relacionadas à Folistatina/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Hipóxia Celular , Linhagem Celular , Proteínas Relacionadas à Folistatina/genética , Janus Quinase 2/metabolismo , Células-Tronco Mesenquimais/patologia , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Ratos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
20.
FASEB J ; 34(1): 1447-1464, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914641

RESUMO

Mitochondrial fission is important in physiological processes, including coordination of mitochondrial and nuclear division during mitosis, and pathologic processes, such as the production of reactive oxygen species (ROS) during cardiac ischemia-reperfusion injury (IR). Mitochondrial fission is mainly mediated by dynamin-related protein 1 (Drp1), a large GTPase. The GTPase activity of Drp1 is essential for its fissogenic activity. Therefore, we aimed to identify Drp1 inhibitors and evaluate their anti-neoplastic and cardioprotective properties in five cancer cell lines (A549, SK-MES-1, SK-LU-1, SW 900, and MCF7) and an experimental cardiac IR injury model. Virtual screening of a chemical library revealed 17 compounds with high predicted affinity to the GTPase domain of Drp1. In silico screening identified an ellipticine compound, Drpitor1, as a putative, potent Drp1 inhibitor. We also synthesized a congener of Drpitor1 to remove the methoxymethyl group and reduce hydrolytic lability (Drpitor1a). Drpitor1 and Drpitor1a inhibited the GTPase activity of Drp1 without inhibiting the GTPase of dynamin 1. Drpitor1 and Drpitor1a have greater potency than the current standard Drp1 GTPase inhibitor, mdivi-1, (IC50 for mitochondrial fragmentation are 0.09, 0.06, and 10 µM, respectively). Both Drpitors reduced proliferation and induced apoptosis in cancer cells. Drpitor1a suppressed lung cancer tumor growth in a mouse xenograft model. Drpitor1a also inhibited mitochondrial ROS production, prevented mitochondrial fission, and improved right ventricular diastolic dysfunction during IR injury. In conclusion, Drpitors are useful tools for understanding mitochondrial dynamics and have therapeutic potential in treating cancer and cardiac IR injury.


Assuntos
Dinaminas , Inibidores Enzimáticos , Traumatismo por Reperfusão Miocárdica , Neoplasias , Células A549 , Animais , Dinaminas/antagonistas & inibidores , Dinaminas/química , Dinaminas/genética , Dinaminas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
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