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1.
Life Sci ; 239: 117016, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678281

RESUMO

The current study aimed to investigate the effects of tetramethylprazine (TMP) on myocardial ischemia/reperfusion (MI/R) injury and its underlying mechanisms. MI/R rat model and hypoxia/reoxygenation (H/R) cardiomyocytes model were established. CK level and LDH activity were detected to evaluate MI/R and H/R injury. Cell viability was determined by cell counting kit-8 (CCK-8) assay. Cell apoptosis were identified by flow cytometry and autophagy were detected by western blot. Treatment with TMP significantly reduced CK level and LDH activity and decreased myocardial infarct size in MI/R rats. TMP reduced autophagy dysfunction induced by MI/R. Moreover, TMP treatment decreased H/R-induced injury and attenuated autophagy dysfunction in cardiomyocytes. Inhibiting autophagic flux with chloroquine (CQ) decreased the cardioprotection exerted by TMP in vivo and in vitro. Additionally, the effects of TMP on the modulation of autophagy were inhibited by LY294002 (a PI3K inhibitor) in H/R cardiomyocytes. Our findings suggested TMP exerted cardioprotection against MI/R injury by decreasing Beclin-1 associated autophagy dysfunction through PI3K pathway.


Assuntos
Autofagia/efeitos dos fármacos , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Pirazinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Creatina Quinase/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Morfolinas/farmacologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/antagonistas & inibidores , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley
2.
Biomed Khim ; 65(5): 398-402, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666412

RESUMO

The experimental study of the cardioprotective effect of uridine, the metabolic precursor of the endogenous activator of mitochondrial ATP-dependent K+-channels (mitoKATP-channels), was performed using the model of myocardial ischemia/reperfusion (I/RP) in rats. Ischemia for 30 min followed by reperfusion for 120 min resulted in a significant decrease in ATP and phosphocreatine (PC) content, intensification of lipid peroxidation (LPO), and inhibition of the antioxidant system (AOS) in cardiomyocytes. Uridine in a dose of 30 mg/kg, administered intravenously prior to reperfusion, had a protective effect on myocardial metabolism in the I/RP zone. It prevented the decrease of ATP and PC, limited the LPO processes, evaluated by the content of lipid hydroperoxides and conjugated dienes, and improved the AOS state by, preventing the decrease of superoxide dismutase (SOD) activity and increasing the content of reduced glutathione (GSH). The mitoKATP-channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg) eliminated the ability of uridine to maintain the ATP level and to exhibit its positive effect on the intensity of the LPO and activity of AOS. The obtained data allow us to conclude that activation of mitoKATP-channels play an important role in the mechanism of the cardioprotective effect of uridine in I/RP damage of myocardium.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Uridina/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/metabolismo , Ácidos Decanoicos , Glutationa/metabolismo , Hidroxiácidos , Peroxidação de Lipídeos , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio , Substâncias Protetoras/farmacologia , Ratos , Superóxido Dismutase/metabolismo
3.
Biochem Cell Biol ; 97(5): 621-629, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31580709

RESUMO

This study investigated the potential effect of n-6/n-3 polyunsaturated fatty acids (PUFA) on inflammation and myocardial ischemic reperfusion injury (MIRI) in rats, together with the underlying protective mechanisms, and screen out most effective ratio of n-6/n-3 within limits. The rats with pre-infarct treatment were distributed among 5 groups according to the n-6/n-3 ratio (36:1; 1:1, 5:1, 10:1, 50:1); for the post-infarct treatment, the rats were distributed among 6 groups, including the control group (36:1) which was subjected to a sham procedure; the model group (36:1); and 4 test groups (n-6/n-3 ratio: 1:1, 5:1, 10:1, 50:1). All of the rats were fed a purple perilla seed oil and safflower oil-based fatty emulsion. The serum levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were determined using enzyme-linked immunosorbent assay. Staining with triphenyl tetrazolium chloride, hematoxylin and eosin, or Masson's trichrome was performed for histological examination. Cardiomyocyte apoptosis was examined by TUNEL assay. Western blotting was performed to examine the expression levels of apoptosis-related proteins and signaling pathway proteins. Our data indicate that in both the pre-infarct treatment and post-infarct treatment, low ratios of n-6/n-3 PUFAs significantly inhibited the levels of serum inflammatory factors, the infarct size of MIRI rats, number of cardiomyocytes undergoing apoptosis, and the expression levels of caspase-3, Bcl-2, and Bax in the MIRI group. Thus a low ratio of n-6/n-3 PUFAs ameliorates inflammation and myocardial ischemic reperfusion injury.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Inflamação/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/administração & dosagem , Ácidos Graxos Ômega-6/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
4.
Acta Cir Bras ; 34(8): e201900802, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618402

RESUMO

PURPOSE: To reveal the function of miR-134 in myocardial ischemia. METHODS: Real-time PCR and western blotting were performed to measure the expression of miR-134, nitric oxide synthase 3 (NOS3) and apoptotic-associated proteins. Lactic dehydrogenase (LDH) assay, cell counting kit-8 (CCK-8), Hoechst 33342/PI double staining and flow cytometry assay were implemented in H9c2 cells, respectively. MiR-134 mimic/inhibitor was used to regulate miR-134 expression. Bioinformatic analysis and luciferase reporter assay were utilized to identify the interrelation between miR-134 and NOS3. Rescue experiments exhibited the role of NOS3. The involvement of PI3K/AKT was assessed by western blot analysis. RESULTS: MiR-134 was high regulated in the myocardial ischemia model, and miR-134 mimic/inhibitor transfection accelerated/impaired the speed of cell apoptosis and attenuated/exerted the cell proliferative prosperity induced by H/R regulating active status of PI3K/AKT signaling. LDH activity was also changed due to the different treatments. Moreover, miR-134 could target NOS3 directly and simultaneously attenuated the expression of NOS3. Co-transfection miR-134 inhibitor and pcDNA3.1-NOS3 highlighted the inhibitory effects of miR-134 on myocardial H/R injury. CONCLUSION: This present work puts insights into the crucial effects of the miR-134/NOS3 axis in myocardial H/R injury, delivering a potential therapeutic technology in future.


Assuntos
Hipóxia/metabolismo , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proliferação de Células/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
5.
Acta Cir Bras ; 34(7): e201900708, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531541

RESUMO

PURPOSE: To investigate the effect of astragaloside IV (As-IV) on myocardial ischemia-reperfusion (I/R) injury in rats and reltaed mechanisms. METHODS: Sixty rats were randomly divided into sham-operated, control I/R and 2.5, 5 and 10 mg/kg As-IV groups, 12 rats in each group. The later three groups were intragastrically administered with As-IV for 7 days, with a dose of 2.5, 5 and 10 mg/kg, respectively. The myocardial I/R injury model was constructed in later four groups. At the end of reperfusion, the cardiac function indexes, serum lactate dehydrogenase (LDH) and creatine kinase (CK) levels, heart weight (HW)/body weight (BW) ratio and infarct size, and expressions of phosphatidylinositol-3 kinase/serine-threonine protein kinase (PI3K/AKT) and glycogen synthase kinase-3ß (GSK-3ß) proteins and the phosphorylated forms (p-AKT, p-GSK-3ß) were determined. RESULTS: Compared with control I/R group, in 5 and 10 mg/kg As-IV groups the left ventricular systolic pressure, fractional shortening and ejection fraction were increased, the left ventricular end-diastolic pressure was decreased, the serum LDH and CK levels were decreased, the HW/BW ratio and myocardial infarct size were decreased, and the p-Akt/Akt ratio and p-GSK-3ß/GSK-3ß ratio were increased (all P < 0.05). CONCLUSION: As-IV can alleviate the myocardial I/R injury in rats through regulating PI3K/AKT/GSK-3ß signaling pathways.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fosforilação , Ratos , Ratos Sprague-Dawley
6.
ACS Appl Mater Interfaces ; 11(34): 30631-30639, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31382735

RESUMO

Acute myocardial infarction, which can be extremely difficult to treat, is the worst deadly disease around the world. Reperfusion is expedient to reverse myocardial ischemia. However, during reperfusion, reactive oxygen species (ROS) produced by myocardial ischemia-reperfusion injury (MIRI) and further cell apoptosis are the most serious challenges to cardiomyocytes. Therefore, searching for reagents that can simultaneously reduce oxidative damage and MIRI-induced apoptosis is the pivotal strategy to rescue injured cardiomyocytes. Nevertheless, current cardioprotective drugs have some shortcomings, such as cardiotoxicity, inadequate intravenous administration, or immature technology. Previous studies have shown that tetrahedral DNA nanostructures (TDNs) have biological safety with promising anti-inflammatory and antioxidative potential. However, the progress that TDNs have made in the biological behavior of cardiomyocytes has not been explored. In this experiment, a cellular model of MIRI was first established. Then, confirmed by a series of experiments, our study indicates that TDNs can significantly decrease oxidative damage and apoptosis by limiting the overexpression of ROS, along with effecting the expression of apoptosis-related proteins. In addition, Western blot analysis demonstrated that TDNs could activate the Akt/Nrf2 signaling pathway to improve the myocardial injury induced by MIRI. Above all, the antioxidant and antiapoptotic capacities of TDNs make them a potential therapeutic drug for MIRI. This study provides new ideas and directions for more homogeneous diseases induced by oxidative damage.


Assuntos
Cardiotônicos , DNA , Depuradores de Radicais Livres , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Nanoestruturas/química , Animais , Apoptose/efeitos dos fármacos , Cardiotônicos/química , Cardiotônicos/farmacologia , Linhagem Celular , DNA/química , DNA/farmacologia , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Int J Mol Sci ; 20(16)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443187

RESUMO

Background: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined. Methods: Adult pigs (30-40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology. Results: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups. Conclusion: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Quinazolinonas/uso terapêutico , Animais , Modelos Animais de Doenças , Ecocardiografia , Feminino , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Projetos Piloto , Suínos , Função Ventricular Esquerda/efeitos dos fármacos
8.
Am J Chin Med ; 47(5): 1057-1073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31327236

RESUMO

Ginkgo biloba extracts (EGb) alleviate myocardial ischemia/reperfusion (MI/R) injury. However, the underlying mechanisms have not yet been characterized. This study aimed to investigate whether activation of large-conductance Ca2+-activated K+ channels at the inner mitochondrial membrane (mitoBKCa) of cardiomyocytes is involved in Ginkgo biloba extract-mediated cardioprotection. Shuxuening injection (SXNI, 12.5ml/kg/d), a widely prescribed herbal medicine containing Ginkgo biloba extracts in China, or vehicle, was administered to C57BL/6 mice via tail vein injection for one week prior to surgical procedures. The mitoBKCa blocker paxilline (PAX) (1ml/kg, 115 nM) was administered via tail vein injection 30min prior to the onset of ischemia. The mice were randomly divided into the following groups: Sham, MI/R, MI/R+SXNI, and MI/R+SXNI+PAX. MI/R was induced by ligating the left anterior descending coronary artery for 30min with subsequent reperfusion for 24h. SXNI pretreatment conferred cardioprotective effects against MI/R injury as evidenced by reduced infarct size, improved cardiac function, and improved mitochondrial function. However, these effects were abrogated by co-administration with PAX. In addition, activation of mitoBKCa by Ginkgo biloba extract EGb761 reduced hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury in vitro through the inhibition of mitochondrial fragmentation, restoration of the mitochondrial membrane potential, decreased generation of superoxide, and inhibition of apoptosis which is associated with alleviating mitochondrial Ca2+ overload. These results indicated that Ginkgo biloba extracts pretreatment protected against MI/R injury via activation of mitoBKCa.


Assuntos
Ginkgo biloba/química , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , China , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo
9.
Mol Cell Biochem ; 461(1-2): 73-80, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31342300

RESUMO

A multi-component solution, containing α-ketoglutaric acid (α-KG), 5-hydroxymethylfurfural (5-HMF), N-acetyl-seleno-L-methionine (NASeLM), and N-acetyl-L-methionine (NALM) as active ingredients, has been tested considering its supposed antioxidative effect with respect to heart transplantations. Oxidative stress was induced on isolated rat hearts through occlusion of a coronary artery and in chicken heart tissue through hydrogen peroxide. Both heart types were analyzed and the oxidative stress markers malondialdehyde (MDA) and carbonyl proteins (CPs) were determined via HPLC/UV-Vis. In both approaches, it was found that treatment with the multi-component solution led to a lower amount of MDA and CPs compared to a negative control treated with Krebs-Ringer solution (KRS). Further investigation on chicken heart tissue identified α-KG as antioxidative component in these experiments. However, numerous factors like arrhythmia, vessel dilatation, and minimization of oxidative stress effects play an important role for successful transplantation. Therefore, the investigated multi-component solution might be a novel approach against oxidative stress situations, for example at ischemia reperfusion injury during heart transplantations.


Assuntos
Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Coração/fisiologia , Animais , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Cardiotônicos/uso terapêutico , Galinhas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Coração/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
10.
Am J Chin Med ; 47(5): 1043-1056, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311299

RESUMO

Baicalein is a natural flavonoid with anti-oxidant activities protecting against ischemia/reperfusion (I/R) injury. Previous studies suggest that oxidative burst early after reperfusion accelerates cell death. We therefore investigated the critical therapeutic window of baicalein by examining the timing of baicalein treatment in relation to its oxidant modulating and cytoprotective effects. Using an established chick cardiomyocyte model of I/R, we administered baicalein at various time points after reperfusion and assessed cell viability and the profiles of reactive oxygen species (ROS), nitric oxide (NO), and Akt phosphorylation. Baicalein administered at the onset of reperfusion resulted in a concentration-dependent reduction of cell death (25 µM 48.2±1.9%, 50µM 43.8±1.5%, 100µM 36.6±2.1%, vs. I/R control 57.3±1.4%, all p<0.05). Baicalein (100µM) timely and effectively scavenged ROS burst and enhanced NO production in the early reperfusion phase. Cotreatment with NO synthase (NOS) inhibitor l-NAME (200µM) partially abrogated the cytoprotective effect. Baicalein (100µM) given after reperfusion lost protective effect in a time-dependent manner with cytoprotection completely lost if >60min. Even with only 15-min delay after reperfusion, the ROS scavenging effect was abolished and the NO enhancing effect markedly reduced. The phosphorylation of Akt, an upstream regulator of eNOS, also diminished as the delay lengthened. In conclusion, baicalein treatment after reperfusion confers cardioprotection in a concentration- and time-dependent manner. The critical therapeutic window lies in the early reperfusion phase, during which ROS scavenging and Akt-eNOS mediated NO signaling are most effective.


Assuntos
Cardiotônicos/farmacologia , Flavanonas/farmacologia , Depuradores de Radicais Livres/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células Cultivadas , Galinhas , Humanos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Oxidantes/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
11.
Biomed Khim ; 65(3): 231-238, 2019 Apr.
Artigo em Russo | MEDLINE | ID: mdl-31258147

RESUMO

The goal of this study was to examine effects of a novel galanin receptor agonist GalR1-3 [bAla14, His15]-galanine 2-15 (G), obtained by automatic solid-phase synthesis, on the metabolic state of the area at risk and the size of acute myocardial infarction (MI) in rats in vivo and evaluate its toxicity in BALB /c mice. In anesthetized rats, regional ischemia was simulated by coronary artery occlusion and then coronary blood flow was restored. The peptide G was administered intravenously (i.v.) with a bolus after a period of regional ischemia in the dose range of 0.25-3.0 mg/kg. The sizes of MI and the activities of creatine kinase-MB (СK-MB) and lactate dehydrogenase (LDH) in blood plasma were estimated. The effect of administration of the optimal dose of G (1.0 mg/kg) on myocardial content of adenine nucleotides (AN), phosphocreatine (PCr), creatine (Cr) and lactate was studied. I.v. administration of G to rats at a dose of 1.0 mg/kg slightly affected hemodynamic parameters, but reduced MI size by 40% and decreased plasma LDH and CK-MB activity by the end of reperfusion compared to control. These effects were accompanied by a significant improvement in energy state of area at risk (AAR) - an increase in myocardial content of ATP, åAN, PCr and åCr, and combined with a decrease in myocardial lactate level compared with the control. Toxicity of peptide G was studied with a single intraperitoneal injection of 0.5-3.0% solution of the peptide substance to mice. The absence of signs of intoxication and death of animals after G injection in the maximum possible dose did not allow determining the value of the average lethal dose. The results indicate therapeutic potential of the peptide G for preventing myocardial ischemia and reperfusion injury and feasibility for further study of its pharmacological properties and mechanisms of action.


Assuntos
Infarto do Miocárdio/patologia , Peptídeos/farmacologia , Receptores de Galanina/agonistas , Animais , Creatina Quinase Forma MB/sangue , Modelos Animais de Doenças , L-Lactato Desidrogenase/sangue , Camundongos , Camundongos Endogâmicos BALB C , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Ratos
12.
Oxid Med Cell Longev ; 2019: 7283683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308876

RESUMO

Antioxidative stress provides a cardioprotective effect during myocardial ischemia/reperfusion (I/R). Previous research has demonstrated that the blockade of transient receptor potential vanilloid 4 (TRPV4) attenuates myocardial I/R injury. However, the underlying mechanism remains unclear. The current study is aimed at investigating the antioxidative activity of TRPV4 inhibition and elucidating the underlying mechanisms in vitro and ex vivo. We found that the inhibiting TRPV4 by the selective TRPV4 blocker HC-067047 or specific TRPV4-siRNA significantly reduces reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels in H9C2 cells exposed to hypoxia/reoxygenation (H/R). Meanwhile, the activity of antioxidative enzymes, particularly superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), is enhanced. Furthermore, after H/R, HC-067047 treatment increases the expression of P-Akt and the translocation of nuclear factor E2-related factor 2 (Nrf2) and related antioxidant response element (ARE) mainly including SOD, GSH-Px, and catalase (CAT). LY294002, an Akt inhibitor, suppresses HC-067047 and specific TRPV4-siRNA-induced Nrf2 expression and its nuclear accumulation. Nrf2 siRNA attenuates HC-067047 and specific TRPV4-siRNA-induced ARE expression. In addition, treatment with LY294002 or Nrf2 siRNA significantly attenuates the antioxidant and anti-injury effects of HC-067047 in vitro. Finally, in experiments on isolated rat hearts, we confirmed the antioxidative stress roles of TRPV4 inhibition during myocardial I/R and the application of exogenous H2O2. In conclusion, the inhibition of TRPV4 exerts cardioprotective effects through enhancing antioxidative enzyme activity and expressions via the Akt/Nrf2/ARE pathway.


Assuntos
Antioxidantes/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Elementos de Resposta Antioxidante/genética , Catalase/metabolismo , Cromonas/farmacologia , Peróxido de Hidrogênio/metabolismo , Masculino , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Fator 2 Relacionado a NF-E2 , Proteína Oncogênica v-akt/antagonistas & inibidores , Proteína Oncogênica v-akt/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pirróis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
13.
Mol Cell Biochem ; 460(1-2): 195-203, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280435

RESUMO

L-Alpha-glycerylphosphorylcholine (GPC) is a widely used food supplement. GPC has been shown to exert beneficial effects in several organs; however, the cardiac effects of GPC have yet to be investigated. The aim of the present study was therefore to map out the effects of GPC on cardiac myocytes, with or without ischemia-reperfusion insult. Neonatal rat cardiac myocytes were treated with GPC at 1, 10, 80, and 100 µM concentrations for 15 min, 3 h, or 24 h, respectively. Cell viability by calcein assay and the degree of oxidative stress by DHE (superoxide level) and H2DCF (total ROS accumulation) staining were measured. In separate experiments, cardiomyocytes were pre-treated with the optimal concentration of GPC for 3 h and then cells were exposed to 4 h of simulated ischemia followed by 2 h of reperfusion (SI/R). Cell viability was measured at the end of the SI/R protocol. In normoxic conditions, the 15-min and the 3-h GPC treatment did not affect cell viability, total ROS, and superoxide levels. Under SI/R conditions, the 3-h GPC treatment protected the cardiac myocytes from SI/R-induced cell death and did not alter the level of oxidative stress. The 24-h GPC treatment in normoxic conditions resulted in significant cell death and increased oxidative stress at each concentration. Here we provide the first evidence for the cytoprotective effect of short-term GPC treatment. However, long-term administration of GPC may exert cytotoxicity in a wide concentration range in cardiac myocytes. These results may draw attention to a comprehensive cardiac safety protocol for the testing of GPC.


Assuntos
Citoproteção/efeitos dos fármacos , Glicerilfosforilcolina/farmacologia , Miócitos Cardíacos/citologia , Animais , Animais Recém-Nascidos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glicerilfosforilcolina/administração & dosagem , Glicerilfosforilcolina/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos Wistar
14.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2566-2571, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359725

RESUMO

This study was to investigate the mechanism of safflower yellow injection for regulating inflammatory response against myocardial ischemia-reperfusion injury( MIRI) in rats. Male Wistar rats were randomly divided into sham operation group,model group,Hebeishuang group,safflower yellow injection high,medium and low dose groups. MIRI model was established by ligating left anterior descending coronary artery. Myocardial histopathological changes were observed by HE staining; myocardial infarct size was detected by TTC staining; content and changes of tumor necrosis factor-α( TNF-α) and interleukin-6( IL-6),serum creatine kinase( CK),aspartate aminotransferase( AST),and lactate dehydrogenase( LDH) were detected by biochemical method or enzyme-linked immunosorbent assay( ELISA). Western blot assay was used to detect the protein expression of Toll-like receptor 4( TLR4) and nuclear factor-κB( NF-κB p65) in myocardial tissues. The results showed that as compared with the sham operation group,the myocardial arrangement of the model group was disordered,with severe edemain the interstitial,significantly increased area of myocardial infarction,increased activities of AST,CK and LDH in serum,and significantly increased contents of TNF-α and IL-6; the expression levels of TLR4 and NF-κB( p65) protein in myocardial tissues were also increased. As compared with the model group,the myocardial tissues were arranged neatlyin the Hebeishuang group and safflower yellow injection high,medium and low dose groups; the edema was significantly reduced; the myocardial infarct size was significantly reduced; the serum AST,CK,LDH activity and TNF-α,IL-6 levels were significantly decreased,and the expression levels of TLR4 and NF-κB( p65) protein in myocardial tissues were decreased. As compared with the Hebeishuang group,the myocardial infarct size was larger in the safflower yellow injection high,medium and low dose groups; the activities of AST,CK and LDH in serum and the contents of TNF-α and IL-6 in serum were higher,but there was no statistically significant difference in the expression levels of TLR4 and NF-κB( p65) protein in tissues. It is suggested that safflower yellow injection has a significant anti-MIRI effect,and its mechanism may be related to the regulation of TLR-NF-κB pathway to inhibit inflammatory response.


Assuntos
Anti-Inflamatórios/farmacologia , Chalcona/análogos & derivados , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Aspartato Aminotransferases/sangue , Chalcona/farmacologia , Creatina Quinase/sangue , Interleucina-6/metabolismo , L-Lactato Desidrogenase/sangue , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
15.
Acta Cir Bras ; 34(5): e201900505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166461

RESUMO

PURPOSE: To evaluate the cardioprotective response of the pharmacological modulation of ß-adrenergic receptors (ß-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. METHODS: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with ß-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with ß-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. RESULTS: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of ß-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of ß-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). CONCLUSION: The pharmacological modulation of ß-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Cardiotônicos/farmacologia , Isoproterenol/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase Forma MB/sangue , Testes de Função Cardíaca , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos Endogâmicos SHR , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
16.
Int J Mol Med ; 44(2): 405-416, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173173

RESUMO

Hydroxysafflor Yellow A (HSYA) may reduce ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms remain unclear. The present study explored the effect and the mechanisms of HSYA on myocardial injury in vivo and in vitro. Myocardial infarct size was assessed by Evans blue/2,3,5­triphenyltetrazoliumchloride staining. Levels of cardiac troponin I (cTnI), interleukin­6 (IL­6), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured using commercial kits. Alteration of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation was determined by fluorescent signals. Apoptosis was detected by terminal deoxynucleotidyl­transferase­mediated dUTP nick­end labeling staining, flow cytometry assay and caspase­3 activity. Expression levels of the apoptosis­associated proteins were detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. In vivo, animals treated with HSYA presented less severe myocardial injury and decreased janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) activity, improved antioxidant capacity and decreased apoptosis. In vitro, compared with the hypoxia (H)/reoxygenation (R) + HSYA group, AG490 and S1491 treatment decreased the releases of cTnI, IL­6 and LDH and enhanced the resistance to oxidative stress by maintaining MMP and decreasing ROS generation. In addition, AG490 and S1491 were also identified to alleviate the H/R­induced apoptosis by inhibiting caspase 3 activity and modulating the expression levels of cleaved caspase­3, tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand, B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein. These data suggested that inactivation of the JAK2/STAT1 pathway strengthened the HSYA­induced protective effect in H/R­induced myocardial injury. In conclusion, the treatment of HSYA was effective in decreasing IR­induced myocardial injury, and this may be largely dependent on the JAK2/STAT1 pathway. Therefore, the present study provided a potential strategy to prevent myocardial I/R injury.


Assuntos
Chalcona/análogos & derivados , Janus Quinase 2/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Quinonas/uso terapêutico , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/uso terapêutico , Chalcona/uso terapêutico , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos Sprague-Dawley
17.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146391

RESUMO

The noble gas helium (He) induces cardioprotection in vivo through unknown molecular mechanisms. He can interact with and modify cellular membranes. Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma-membrane-containing caveolin (Cav) proteins that are critical in protection of the heart. Mice (C57BL/6J) inhaled either He gas or adjusted room air. Functional measurements were performed in the isolated Langendorff perfused heart at 24 h post He inhalation. Electron paramagnetic resonance spectrometry (EPR) of samples was carried out at 24 h post He inhalation. Immunoblotting was used to detect Cav-1/3 expression in whole-heart tissue, exosomes isolated from platelet free plasma (PFP) and membrane fractions. Additionally, transmission electron microscopy analysis of cardiac tissue and serum function and metabolomic analysis were performed. In contrast to cardioprotection observed in in vivo models, the isolated Langendorff perfused heart revealed no protection after He inhalation. However, levels of Cav-1/3 were reduced 24 h after He inhalation in whole-heart tissue, and Cav-3 was increased in exosomes from PFP. Addition of serum to muscle cells in culture or naïve ventricular tissue increased mitochondrial metabolism without increasing reactive oxygen species generation. Primary and lipid metabolites determined potential changes in ceramide by He exposure. In addition to direct effects on myocardium, He likely induces the release of secreted membrane factors enriched in caveolae. Our results suggest a critical role for such circulating factors in He-induced organ protection.


Assuntos
Cardiotônicos/farmacologia , Caveolinas/metabolismo , Coração/efeitos dos fármacos , Hélio/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Cardiotônicos/uso terapêutico , Cavéolas/efeitos dos fármacos , Cavéolas/metabolismo , Caveolinas/sangue , Caveolinas/genética , Células Cultivadas , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Hélio/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle
18.
J Biosci ; 44(2)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31180066

RESUMO

Ischemia-reperfusion (IR) is one of the significant medical problems in China. Triphenyltetrazolium chloride (TTC) staining is used to detect the status of the infarct size, and real-time PCR and western blotting are used to detect expressions of genes. TUNEL assay has been used to detect apoptosis. Using a tree shrew myocardial IR model, we found that in the reperfusion period, resina draconis (RD) treatment reduced the infarct size by TTC staining, and significantly enhanced the superoxide dismutase expression and down-regulated the malondialdehyde concentration in a dose-dependent manner. In hearts showing IR, Bax was increased and Bcl-2 was reduced, and RD treatment inhibited the IR-induced Bax expression and up-regulated the IR suppressed level of Bcl-2. TUNEL assay showed that IR induced the apoptosis of myocardial cells, and RD treatment suppressed the IR-induced apoptosis. CHOP and GRP78 were also upregulated in IR hearts, and RD treatment could significantly attenuate the CHOP and GRP78 levels compared with IR group. We further found that IR decreased the miR-423-3p expression and upregulated its target gene ERK both in mRNA and protein levels, and RD treatment upregulated miR-423-3p expression and downregulated ERK expression compared with the IR group. Importantly, miR-423-3p mimics inhibited IR increased ERK, CHOP and GRP78 expressions, and enhanced IR decreased Bcl-2 expression, and inhibited the IR-induced apoptosis of myocardial cells. The findings of this study suggest that RD treatment inhibited the endoplasmic reticulum induced apoptosis of myocardial cells via regulating miR-423-3p/ERK signaling pathway in a tree shrew myocardial IR model.


Assuntos
Cardiotônicos/farmacologia , Dracaena/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Resinas Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Cardiotônicos/isolamento & purificação , Modelos Animais de Doenças , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Resinas Vegetais/isolamento & purificação , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Tupaiidae , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismo
19.
Bioelectrochemistry ; 129: 170-178, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31181439

RESUMO

Our aim was to investigate if the cardioplegic solution HTK can be improved by the addition of the ROS scavenger melatonin. 158 guinea pig hearts without (UI80) or with HTK protection (HTK80) were investigated in ischemia/reperfusion experiments. Ischemia lasted 80 min at 30 °C. Melatonin was given before ischemia (UI80 + M1, HTK80 + M1) or before and after ischemia (UI80 + M2, HTK80 + M2). We measured the left ventricular developed pressure (LVDP), diastolic pressure (LVPmin), cardiac rhythm (VC-RR), time of electrical cell uncoupling (t-in) and recovery (t-ret), intracellular Ca++ [Ca++], and postischemic ROS. After 45 min reperfusion, LVDP in UI80 was significantly higher than in HTK80 (p < .01). Compared to UI80, the postischemic ROS burst was slightly smaller in HTK80 and significantly smaller in HTK80 + M1 and HTK80 + M2 (p < .05). Melatonin had no effect on LVPmin, t-in, t-ret, [Ca++], and on LVDP in groups UI80 + M1 and HTK80 + M1, improved slightly VC-RR (n. s.) but significantly decreased LVDP in the groups UI80 + M2 and HTK80 + M2 (p < .01). With melatonin we were able to attenuate the postischemic ROS burst, but the tissue damage by ROS seemed to be less important for the chosen ischemia condition because melatonin was unable to improve the functional recovery during reperfusion of HTK protected hearts.


Assuntos
Soluções Cardioplégicas/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Parada Cardíaca Induzida/métodos , Coração/efeitos dos fármacos , Melatonina/uso terapêutico , Traumatismo por Reperfusão Miocárdica/terapia , Animais , Feminino , Cobaias , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/cirurgia
20.
Oxid Med Cell Longev ; 2019: 5793867, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182995

RESUMO

Aims: Myocardial ischemia/reperfusion (I/R) injury is a leading cause of cardiomyocyte loss and subsequent ventricular dysfunction after restoring the coronary blood flow and contributes to considerable increase in morbidity and mortality. Resveratrol has been declared to confer cardioprotection against in vivo and ex vivo myocardial I/R injury. Here, we have sought to investigate the effects of preconditioning with resveratrol on myocardial I/R damage across the small animal studies. Methods and Results: The MEDLINE, Google Scholar, PubMed, and Cochrane databases were searched for preclinical studies investigating resveratrol vs. vehicle published from the inception to July 2018. Eventually, 10 in vivo and 7 ex vivo studies with 261 animals (130 for resveratrol; 131 for vehicle) were included for meta-analysis. Pooled estimates for primary outcomes demonstrated that pretreatment with resveratrol significantly reduced the infarct size after myocardial I/R injury irrespective of in vivo (weighted mean difference (WMD): -13.42, 95% CI: -16.63 to -10.21, P ≤ 0.001) or ex vivo (WMD: -15.05, 95% CI: -18.23 to -11.86, P ≤ 0.001) studies. Consistently, stratified analysis according to the reperfusion duration, route of administration, or timing regimen of pretreatment all showed the infarct-sparing benefit of resveratrol. Metaregression did not indicate any difference in infarct size based on species, sample size, state, route of administration, reperfusion duration, and timing regimen of pretreatment. Meanwhile, sensitivity analysis also identified the cardioprotection of resveratrol with robust results in spite of significant heterogeneity. Conclusions: Preconditioning with resveratrol appears to prevent the heart from I/R injury in comparison with vehicle, as evidenced by limited infarct size in a preclinical setting. Studies with large animals or randomized controlled trials will add more evidence and provide the rationale for clinical use.


Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
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