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1.
Cell Physiol Biochem ; 53(6): 961-981, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820856

RESUMO

BACKGROUND/AIMS: We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin. METHODS: Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction. RESULTS: Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects. CONCLUSION: Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.


Assuntos
Apoptose/efeitos dos fármacos , Infarto do Miocárdio/patologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticagrelor/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Endoglina/genética , Endoglina/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/farmacologia , Cloridrato de Prasugrel/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Ticagrelor/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
2.
Acta Cir Bras ; 34(11): e201901104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31859817

RESUMO

PURPOSE: Myocardial ischemia/reperfusion (Ml/R) injury is a leading cause of damage in cardiac tissues, with high rates of mortality and disability. Biochanin A (BCA) is a main constituent of Trifolium pratense L. This study was intended to explore the effect of BCA on Ml/R injury and explore the potential mechanism. METHODS: In vivo MI/R injury was established by transient coronary ligation in Sprague-Dawley rats. Triphenyltetrazolium chloride staining (TTC) was used to measure myocardial infarct size. ELISA assay was employed to evaluate the levels of myocardial enzyme and inflammatory cytokines. Western blot assay was conducted to detect related protein levels in myocardial tissues. RESULTS: BCA significantly ameliorated myocardial infarction area, reduced the release of myocardial enzyme levels including aspartate transaminase (AST), creatine kinase (CK-MB) and lactic dehydrogenase (LDH). It also decreased the production of inflammatory cytokines (IL-1ß, IL-18, IL-6 and TNF-α) in serum of Ml/R rats. Further mechanism studies demonstrated that BCA inhibited inflammatory reaction through blocking TLR4/NF-kB/NLRP3 signaling pathway. CONCLUSION: The present study is the first evidence demonstrating that BCA attenuated Ml/R injury through suppressing TLR4/NF-kB/NLRP3 signaling pathway-mediated anti-inflammation pathway.


Assuntos
Cardiotônicos/farmacologia , Genisteína/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , NF-kappa B/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Aspartato Aminotransferases/sangue , Western Blotting , Creatina Quinase/sangue , Citocinas/sangue , Lactato Desidrogenases/sangue , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
3.
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
4.
Rev Cardiovasc Med ; 20(3): 187-197, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601093

RESUMO

Myocardial ischemia-reperfusion (I/R) injury is leading cause of death worldwide. miR-34a-5p was up-regulated in myocardial ischemia-reperfusion injury rats. We aim to explore how miR-34a-5p inhibition protected myocardium against I/R injury in both cell and animal models. In vivo rat and in vitro cell model were firstly constructed. quantitative real-time polymerase chain reaction was employed to investigate expression of miR-34a-5p and its target genes. Functional assays were conducted to detect the impact of miR-34a-5p on myocardial I/R injury. Enzyme-linked immunosorbent assay was performed to validate the expression levels of marker proteins of ischemia-reperfusion I/R-induced myocardial injury. MTT was performed to assess the cell viability and flow cytometry was utilized to detect cell apoptosis and reactive oxygen species accumulation. The interaction between miR-34a-5p and Notch Receptor 1 were also examined through luciferase reporter assay. miR-34a-5p was up-regulated post-reperfusion at rat myocardium. miR-34a-5p inhibitor attenuated myocardial ischemia-reperfusion injury, as shown by decreasing apoptosis rate, reducing infarct size and reactive oxygen species accumulation. In in vitro cell model, miR-34a-5p inhibitor also promoted cell proliferation, inhibited cell apoptosis and reactive oxygen species accumulation through targeting Notch Receptor 1 signaling. Our results revealed that miR-34a-5p knocking down attenuated myocardial I/R injury by promoting Notch Receptor 1 signaling-mediated inhibition of reactive oxygen species accumulation and cell apoptosis. Hence, miR-34a-5p might be a potential target for treatment of myocardial ischemia-reperfusion injury.


Assuntos
Antagomirs/genética , Apoptose , MicroRNAs/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio , Receptor Notch1/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Receptor Notch1/genética , Transdução de Sinais
5.
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
6.
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
7.
Transplant Proc ; 51(6): 2060-2065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399184

RESUMO

OBJECTIVE: To explore the protective effect and underlying mechanism of allicin (ALC) on myocardial ischemia reperfusion (MI/R) injury in rats. METHODS: The model of MI/R injury in rats was induced by ligating the left anterior descending branch of the coronary artery. Thirty male Sprague-Dawley rats were randomly divided into 3 equal groups (n = 10): sham group, MI/R injury group, and ALC precondition group. Enzyme-linked immunosorbent assay was used to examine the expression of cardiac troponin I, CK-MB, interleukin-6, tumor necrosis factor-α, and interleukin-8 in the rats' serum. Hematoxylin and eosin staining was used to observe the myocardial pathologic morphology. A physiological recorder was used to measure cardiac systolic and diastolic function. Western blot analysis was used for detecting the expression of p38 and p-p38 in myocardium. The content of malondialdehyde and the activity of superoxide dismutase, catalase, and glutathione peroxidase in myocardium were examined by automatic analysis with the thiobarbituric acid chromogenic and dinitrobenzoic acid methods, respectively. RESULTS: ALC can significantly decrease the expression of cardiac troponin I, CK-MB, interleukin-6, tumor necrosis factor-α, and interleukin-8 in the serum and reduce the myocardial pathologic injury and the expression of malondialdehyde and p-p38 in myocardial tissue. Moreover, ALC can upregulate the activity of superoxide dismutase, catalase, and glutathione peroxidase and improve myocardial systolic and diastolic function with no influence on the expression of p38. CONCLUSION: ALC can protect rats against MI/R injury by suppressing inflammation and oxidative stress. The mechanism is associated with alleviating the activation of p38 signaling.


Assuntos
Coração/efeitos dos fármacos , Inflamação/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia , Animais , Inflamação/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Scand Cardiovasc J ; 53(6): 329-336, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31455109

RESUMO

Objectives. Although deuterium oxide (D2O) has preservative property on the extracted organ, whether D2O also protects the in situ myocardial injury remains unknown. Using cardiac microdialysis, local administration of D2O through dialysis probe was applied in situ rat heart. We examined the effect of the D2O on the myocardial injury induced ischemia, reperfusion, and chemical hypoxia. Methodology. We measured dialysate myoglobin levels during 30 min of coronary occlusion and reperfusion in the absence and presence of D2O. Furthermore, to confirm the effect of D2O on NaCN induced myocardial injury, we measured the dialysate myoglobin levels with local perfusion of NaCN in the absence and presence of D2O. Results. The dialysate myoglobin levels increased from 177 ± 45 ng/mL at baseline to 3030 ± 1523 ng/mL during 15-30 min of coronary occlusion and further increased to 8588 ± 1684ng/mL at 0-15 min of reperfusion. The dialysate myoglobin levels with 60 min local perfusion of NaCN increased to 1214 ± 279 ng/mL. D2O attenuated myocardial myoglobin release during 15-30 min of coronary occlusion and 0-30 min of reperfusion and 15-60 min of local perfusion of NaCN. Conclusions. D2O might have a beneficial effect of myocardium against ischemia, reperfusion and chemical hypoxia.


Assuntos
Óxido de Deutério/farmacologia , Cardiopatias/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/patologia , Animais , Modelos Animais de Doenças , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Mioglobina/metabolismo , Ratos Sprague-Dawley , Cianeto de Sódio , Fatores de Tempo
9.
Artif Cells Nanomed Biotechnol ; 47(1): 3511-3516, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31432688

RESUMO

The aim of this study was to investigate whether lncRNA TUG1 could mediate the progression of ischemia-reperfusion injury following acute myocardial infraction. Mouse cardiomyocytes HL-1 cells were subjected to oxygen glucose deprivation followed by reperfusion (OGD/R) to induce myocardial I/R injury. The expression of TUG1 was detected by real-time PCR. Overexpression or down expression of TUG1 was performed in mouse HL-1 cardiomyocytes. The myocardial cell viability and apoptosis were respectively detected. In addition, the expression levels of inflammatory factors, apoptosis-related proteins and HMGB1 proteins were detected. Besides, an inhibitor of HMGB1 was used to treat cells to verify the relationship between TUG1 and HMGB1 protein. The expression of TUG1 was significantly up-regulated in OGD/R-induced myocardial HL-1 cells. The overexpression of TUG1-induced inflammation and apoptosis in OGD-R-induced myocardial HL-1 cells. Knock down of TUG1 protected OGD/R-induced myocardial I/R injury by inhibiting HMGB1 expression. Suppression of lncRNA TUG1 may prevent myocardial I/R injury following acute myocardial infarction via inhibiting HMGB1 expression.


Assuntos
Proteína HMGB1/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/patologia , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Linhagem Celular , Regulação da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Glucose/deficiência , Camundongos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Oxigênio/metabolismo
10.
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
11.
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
12.
Phytomedicine ; 63: 153035, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377586

RESUMO

OBJECTIVE: Baicalin, which is isolated from Scutellariae Radix, has been shown to possess therapeutic potential for different diseases. Cardiac microvessel injury in myocardial ischemia-reperfusion (IR) has been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of baicalin on nitric oxide production and the necroptosis of cardiac microvascular endothelial cells (CMECs) in myocardial IR injury. This study was designed to investigate the contribution of baicalin to repressing necroptosis and preventing IR-mediated CMEC dysfunction. MATERIALS AND METHODS: Indicators of ventricular structure and function were measured by an echocardiographic system. An MTT assay was performed to assess cell viability. Nitrite detection was performed to detect nitric oxide content, and cGMP content was determined using a commercially available cGMP complete ELISA kit. Morphology and molecular characteristics were detected by electron micrographs, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. RESULT: Our results demonstrated that baicalin significantly improved cardiac function, decreased the myocardial infarction area, and inhibited myocardial cell apoptosis. Moreover, baicalin had a protective effect on cardiac microvessels and promoted the production of nitric oxide (NO) and the level of cGMP in rats that underwent myocardial IR injury. The results of the in vitro experiments showed that baicalin markedly improved cell activity and function in CMECs exposed to hypoxia-reoxygenation (HR). Further experiments indicated that baicalin supplementation suppressed the protein expression of RIP1, RIP3 and p-MLKL to interrupt CMEC necroptosis. In addition, baicalin promoted the production of NO via activating the PI3K-AKT-eNOS signaling pathway. Taken together, our results identified the PI3K-AKT-eNOS axis as a new pathway responsible for reperfusion-mediated microvascular damage. CONCLUSION: Baicalin protected CMECs in IR rats by promoting the release of NO via the PI3K-AKT-eNOS pathway and mitigated necroptosis by inhibiting the protein expression of RIP1, RIP3 and p-MLKL.


Assuntos
Cardiotônicos/farmacologia , Flavonoides/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
13.
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
14.
Rev Cardiovasc Med ; 20(2): 59-71, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31344998

RESUMO

Remote ischemic conditioning of the heart (including pre-, per-, and post-conditioning) is a phenomenon where short episodes of non-lethal ischemia in the distant vessels within the heart or distant organs from the heart protects the myocardium against sustained ischemia/reperfusion injury. Several pathways have been proposed to be involved in the mechanisms of Remote ischemic conditioning. While triggers of Remote ischemic conditioning act in preconditioned areas, its mediators transduce protective signals via humoral or neuronal pathways to the heart. Remote ischemic conditioning is mediated via receptor and nonreceptor signaling through secondary mediators, which transfer the signal within the cardiomyocyte and activate cardioprotective pathways that lead to higher resistance of the heart to ischemia/reperfusion. Apparently, identification of endogenous signal molecules involved in the mechanisms of Remote ischemic conditioning have therapeutic implications in the management of patients suffering from myocardial ischemia through the development of diverse beneficial effects. Recently, different non-coding RNAs such as microRNAs or long non-coding RNAs have been identified as emerging factors that trigger protective mechanisms in the heart. These non-coding RNAs are transferred to the heart via extracellular vesicles that exert remote cardioprotection. This review is intended to summarize the existing knowledge about the potential role of extracellular vesicles as humoral transmitters of Remote ischemic conditioning and emphasize the involvement of non-coding RNAs in the mechanism of cardioprotection by Remote ischemic conditioning.


Assuntos
Vesículas Extracelulares/metabolismo , Pós-Condicionamento Isquêmico/métodos , Precondicionamento Isquêmico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , RNA não Traduzido/metabolismo , Animais , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Regulação da Expressão Gênica , Humanos , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , RNA não Traduzido/genética , Transdução de Sinais
15.
Inflamm Res ; 68(10): 867-876, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312857

RESUMO

OBJECTIVES: A drastic reduction in myocardial cell apoptosis plays a crucial role in the treatment/management of myocardial infarction, a major cardiovascular health challenge confronting the world, especially the Western world. Accumulating evidence indicates that the cardiotoxicity caused by the apoptotic machinery is partly regulated by miRNAs. The aim of this research is to investigate the role of miR-138-5p on hypoxia/reperfusion-induced heart injury. METHODS: The expression of miR-138-5p was determined in heart tissue from myocardial infarction patients and rats. Rats were transfection with a miR-138-5p inhibitor to silence miR-138-5p. The cardiac function of rats was detected via echocardiography. SIRT1 and PGC-1α expression in cardiac infarction was detected via quantitative Real-time PCR (qPCR) and Western blot analysis, while the TUNEL assay was used to determine myocardial apoptosis. RESULTS: Our observations showed that miR-138-5p expression was upregulated after the induction of myocardial infarction. The miR-138-5p inhibitor significantly improved cardiac function, increased the expression of SIRT1 and PGC-1α, and decreased the rate of myocardial apoptosis, whereas siRNA-SIRT1 reversed these protective effects. CONCLUSIONS: In conclusion, our study demonstrated that miR-138-5p could promote cardiac ischemia injury via inhibition of the silent information regulator 1 and peroxisome proliferator-initiated receptor gamma and coactivator 1 alpha (SIRT1-PGC-1α) axis.


Assuntos
Hipóxia , MicroRNAs , Traumatismo por Reperfusão Miocárdica , Animais , Células HEK293 , Humanos , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , MicroRNAs/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Sirtuína 1/genética , Função Ventricular Esquerda
16.
Life Sci ; 232: 116658, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310758

RESUMO

AIMS: To investigate the cardioprotective effects of hypothermic (25 °C) reperfusion on ischemia/reperfusion injury and the role of transient potential channel M8 (TRPM8) in this process. MAIN METHODS: Western blot and real-time PCR were used to monitor the expression of TRPM8 in myocardium. Myocardial ischemia/reperfusion injury was induced by 30 min of global ischemia followed by 120 min of reperfusion in Langendorff-perfused hearts from Sprague-Dawley rats. The reperfusion was either normothermic (37 °C) or hypothermic (25 °C). Infarct size and left ventricular function were assessed, and lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) in the coronary effluent were measured spectrophotometrically, and cardiomyocyte apoptosis was detected by TUNEL assay. The expression of TRPM8, Bcl-2, Bax, cleaved capspase-3, RhoA, and ROCK2 was quantified. KEY FINDINGS: TRPM8 protein and mRNA were expressed in rat myocardium. Hypothermic reperfusion decreased the infarct size, LDH activity, MDA content, apoptosis, and expression of Bax, cleaved caspase-3, RhoA, and ROCK2 compared with normothermic reperfusion. These effects were associated with improved recovery of left ventricular contractility, and were reduced by BCTC, a TRPM8 antagonist. Ischemia/reperfusion injury and the increased expression of Bax, caspase-3, RhoA, and ROCK2 induced by normothermic reperfusion were reduced by Icilin, a TRPM8 agonist. SIGNIFICANCE: Hypothermic reperfusion at 25 °C has cardioprotective effects against ischemia/reperfusion injury via activation of TRPM8 to inhibit the oxidative stress-related RhoA/ROCK2 signal pathway.


Assuntos
Hipotermia/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Canais de Cátion TRPM/metabolismo , Animais , Apoptose , Hemodinâmica , L-Lactato Desidrogenase/metabolismo , Masculino , Proteínas Musculares/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/enzimologia , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley
17.
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
18.
Eur J Pharmacol ; 858: 172520, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278893

RESUMO

The metabolic disorder of succinate in myocardial tissue during ischemia-reperfusion can lead to the myocardial oxidative injury. The activation of succinate dehydrogenase (SDH) plays a vital role in the process. Silent information regulator 5 (Sirt5), a nicotinamide adenine dinucleotide (NAD)-dependent desuccinylase, desuccinylates and inactivates SDH thus exerting a protective effect on the myocardium. This research was designed to investigate whether exogenous NAD protects the myocardium from the ischemia-reperfusion-induced oxidative injury through regulating Sirt5-SDH pathway and succinate metabolism. We first found that myocardial total NAD level was remarkably increased with NAD treatment (10 mg/kg) for 14 days. NAD administration significantly decreased the lactate dehydrogenase (LDH) level in coronary leakage, decreased the malondialdehyde (MDA) level and increased the reduced glutathione/oxidized glutathione disulfide ratio (GSH/GSSG) in myocardial tissue. In addition, NAD treatment effectively attenuated the depression of cardiac function in the isolated rat hearts after ischemia-reperfusion. Furthermore, we found that exogenous NAD attenuated the succinate accumulation during ischemia and decreased its depleting rate during reperfusion. We also found that NAD administration had no obvious effects on myocardial Sirt5 and SDH-a expressions. However, the results of immunofluorescence showed that Sirt5 and SDH-a interacted in ischemia-reperfused myocardium. Utilizing co-immunoprecipitation method, we found that NAD administration promoted the Sirt5 and SDH-a interaction and decreased the succinylation level of SDH-a. These results implied that exogenous NAD administration promoted Sirt5-mediated SDH-a desuccinylation and decreased the activity of SDH-a, which attenuated the succinate accumulation during ischemia and its depleting rate during reperfusion and finally alleviated reactive oxygen species generation.


Assuntos
Traumatismo por Reperfusão Miocárdica/metabolismo , NAD/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sirtuínas/metabolismo , Succinato Desidrogenase/metabolismo , Ácido Succínico/metabolismo , Animais , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , NAD/administração & dosagem , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Life Sci ; 232: 116632, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278944

RESUMO

AIMS: The inflammation modulation effects of mesenchymal stromal cell-derived exosomes (MSC-EXO) are well established. We aimed to explore the mechanism behind the inflammatory responses of numerous exosomal cargo molecules that have been neglected in molecular biology research, and to develop an exosomal cargo delivery system that can exert a stronger therapeutic effect on myocardial ischemia-reperfusion (I/R) injury. MAIN METHODS: Computational approaches were used to identify key exosomal miRNAs and their downstream mRNAs that are expressed in the inflammatory response. Direct interactions between miRNA-181a and the c-Fos mRNA complex were confirmed by luciferase reporter assay. MSC-EXO carrying miRNA-181a-overexpressing lentiviruses were intramyocardially injected into a mouse model of myocardial I/R injury. I/R progression was evaluated through echocardiography and immunofluorescence microscopy. KEY FINDINGS: miRNA-181a provided substantial coverage against a host of immune-related genes through the miRNA-mRNA network. miRNA-181a delivery by MSC-EXO combined the immune-suppressing effect of miRNA-181a and the cell targeting capability of MSC-EXO to exert a stronger therapeutic effect on myocardium I/R injury. SIGNIFICANCE: We showed the potential of MSC-EXO as a tool for the specific delivery of small RNAs in vivo. This study shed new light on the potential application of miRNA-181a-overexpressing MSC-EXO as a therapeutic strategy for myocardial I/R injury.


Assuntos
Células-Tronco Mesenquimais/metabolismo , MicroRNAs/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Exossomos , Humanos , Inflamação/terapia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo
20.
J Neuroinflammation ; 16(1): 139, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31287006

RESUMO

BACKGROUND: Sympathetic overactivation and inflammation are two major mediators to post-myocardial ischemia-reperfusion (I/R)-induced ventricular arrhythmia (VA). The vicious cycle between microglia and sympathetic activation plays an important role in sympathetic hyperactivity related to cardiovascular diseases. Recently, studies have shown that microglial activation might be attenuated by light-emitting diode (LED) therapy. Therefore, we hypothesized that LED therapy might protect against myocardial I/R-induced VAs by attenuating microglial and sympathetic activation. METHODS: Thirty-six male anesthetized rats were randomized into four groups: control group (n = 6), LED group (n = 6), I/R group (n = 12), and LED+I/R group (n = 12). I/R was generated by left anterior descending artery occlusion for 30 min followed by 3 h reperfusion. ECG and left stellate ganglion (LSG) neural activity were recorded continuously. After 3 h reperfusion, a programmed stimulation protocol was conducted to test the inducibility of VA. Furthermore, we extracted the brain tissue to examine the microglial activation, and the peri-ischemic myocardium to examine the expression of NGF and inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α). RESULTS: As compared to the I/R group, LED illumination significantly inhibited the LSG neural activity (P < 0.01) and reduced the inducibility of VAs (arrhythmia score 4.417 ± 0.358 vs. 3 ± 0.3257, P < 0.01) in the LED+I/R group. Furthermore, LED significantly attenuated microglial activation and downregulated the expression of inflammatory cytokines and NGF in the peri-infarct myocardium. CONCLUSIONS: LED therapy may protect against myocardial I/R-induced VAs by central and peripheral neuro-immune regulation.


Assuntos
Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/terapia , Neuroimunomodulação/fisiologia , Fototerapia/métodos , Fibrilação Ventricular/imunologia , Fibrilação Ventricular/terapia , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Neuroimunomodulação/efeitos da radiação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fibrilação Ventricular/metabolismo
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