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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 625-630, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537248

RESUMO

Objective To investigate the effect of homocysteine (Hcy) on the cardiomyocytes cultured in vitro, and to analyze the role of folic acid in DNA methylation to explore the protective effect and mechanism of folic acid during Hcy exposure of H9C2 cardiomyocytes. Methods H9C2 cells were treated with Hcy at different concentrations (0, 0.5, 1, 2) mmol/L for 24 hours. Cell viability was tested by CCK-8 assay. The apoptosis was detected by flow cytometry. H9C2 cells were divided into 2 mmol/L Hcy group, 0.1 mmol/L folic acid combined with 2 mmol/L Hcy group, 0.1 mmol/L folic acid group and DMSO control group. The above corresponding treatment lasted 24 hours. Then we detected the cell viability and apoptosis. The total DNA methylation level was determined by MethylFlash ELISA kit. DNMT1, DNMT3a, DNMT3b mRNA and protein expression were detected by real-time quantitative PCR and Western blot analysis. Results The number of H9C2 cells treated with different concentrations of Hcy for 24 hours decreased with the increase of Hcy concentration. Compared with the control group, the activity and apoptosis of the cells in the 2 mmol/L Hcy treatment group were reduced, and the number of cells in the folic acid combined with Hcy treatment group was significantly higher than that in the Hcy treatment group. Compared with the other groups, the total apoptosis rate of Hcy treatment group increased, methylation level decreased significantly, and the level of DNA methylation increased in the folic acid combined with Hcy treatment group. The level of DNMT1 mRNA significantly increased only in the folic acid treatment group, and the levels of DNMT1, DNMT3a and DNMT3b were not significantly changed. Conclusion Folic acid can relieve the damage of Hcy to myocardial cells by DNA methylation.


Assuntos
Apoptose , Metilação de DNA , Ácido Fólico/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Homocisteína , Ratos
2.
Adv Exp Med Biol ; 1155: 451-462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468422

RESUMO

Objective To determine whether taurine has protective effects on chicken myocardial apoptosis induced by hypoxic condition through inhibiting calpain-1 derived mitochondrial apoptotic pathway. Methods Chicken primary embryonic myocardial cells were isolated and cultured at 37 °C under a 5% CO2 atmosphere. Firstly the optimum concentration of taurine or PD150606 was chosen by detecting the cell viability. Chicken cardiomyocytes were cultured in 95% N2-5% CO2 atmosphere for 12 h to produce hypoxic conditions. Before hypoxic treatment, 10 mM taurine and 10 uM PD150606 (a specific calpains inhibitor) were added separately or together. The cell apoptosis was detected by acridine orange/ethidium bromide (AO/EB) double staining. Western blotting was used to determine the protein expressions of calpain-1, cytochrome c, Bcl-2, procaspase-9 and procaspase-3 in the cardiomyocytes. Results Taurine administration effectively attenuated the myocardial apoptosis under hypoxic condition, reduced the calpain-1 protein level. In addition, pre-treated taurine could up-regulate the protein expressions of Bcl-2 and procaspase-3 in hypoxic myocardial cells, down-regulate protein expression levels of cytochrome c and procaspase-9. Moreover, taurine exhibited same inhibition effect as PD150606 on the cell apoptosis and proteins express under hypoxic condition. Conclusions Taurine could attenuate the chicken cardiomyocyte apoptosis impaired by hypoxia through inhibiting calpian-1-derived mitochondrial apoptotic pathway in vitro.


Assuntos
Apoptose , Calpaína/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Taurina/farmacologia , Acrilatos/farmacologia , Animais , Hipóxia Celular , Células Cultivadas , Galinhas , Mitocôndrias
3.
Life Sci ; 232: 116635, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283925

RESUMO

AIMS: The pathological cardiac hypertrophy will develop into heart failure, which has no effective treatment currently. Previous studies have proved that microRNAs (miRNAs) participate in the development of cardiac hypertrophy and regulate the pathological progress. In this study, we want to investigate the role of microRNA-92b-3p (miR-92b-3p) in cardiomyocyte hypertrophy and the mechanisms involved. MATERIALS AND METHODS: Neonatal mouse ventricular cells (NMVCs) were isolated from the hearts of 1-3-d-old newborn C57BL6 mice. The isolated NMVCs were induced hypertrophic phenotype by Angiotensin-II (Ang-II) and the cell size was examined by FITC-phalloidin staining assay. The expression of miR-92b-3p was determined by quantitative real-time PCR (qRT-qPCR). MRNA and protein level of ß-MHC, ACTA1 and HAND2 in NMVCs transfected with miR-92b-3p mimic and inhibition were assessed by RT-qPCR assay and western blot assay, respectively. Dual luciferase assay was used to verify the interaction between miR-92b-3p and the 3'-untranslated region (UTR) of HAND2 gene. KEY FINDINGS: MiR-92b-3p and HAND2 were significantly increased in Ang-II-induced NMVCs. Overexpression of miR-92b-3p can ameliorate Ang-II-induced cardiomyocyte hypertrophy. MiR-92b-3p negatively regulated HAND2 expression at the transcriptional level. Both miR-92b-3p mimic and HAND2 siRNA could efficiently inhibit Ang-II-induced hypertrophy in mouse cardiomyocytes. SIGNIFICANCE: MiR-92b-3p inhibits Ang-II-induced cardiomyocyte hypertrophy via targeting HAND2.


Assuntos
Angiotensina II/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/patologia , Regiões 3' não Traduzidas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Modelos Animais de Doenças , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Ventrículos do Coração/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
4.
Phytochemistry ; 166: 112065, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31362147

RESUMO

Ten undescribed neo-clerodane diterpenoids, named hispanins A-J, together with six known ones, were isolated from the aerial parts of Salvia hispanica L. Their structures were established by extensive spectroscopic analysis. The absolute configurations of the undescribed compounds were determined by the ECD data and single crystal X-ray diffraction analysis. Hispanins B and C represented the first neo-clerodane diterpenoids with a unique oxygen bridge between C-19 and C-20. All isolated compounds were evaluated for their protective effects against H2O2-induced cardiomyocyte injury. Five of these compounds showed significant cardioprotective effects.


Assuntos
Cardiotônicos/química , Cardiotônicos/farmacologia , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Componentes Aéreos da Planta/química , Salvia/química , Animais , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos
5.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1876-1881, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342716

RESUMO

This study is aimed to investigate the intervention effect and possible mechanism of ophiopogonin D( OPD) in protecting cardiomyocytes against ophiopogonin D'( OPD')-induced injury,and provide reference for further research on toxicity difference of saponins from ophiopogonins. CCK-8 assay was used to evaluate the effect of OPD and OPD' on cell viability. The effect of OPD on OPD'-induced cell apoptosis was measured by flow cytometry. Morphologies of endoplasmic reticulum were observed by endoplasmic reticulum fluorescent probe. PERK,ATF-4,Bip and CHOP mRNA levels were detected by Real-time quantitative polymerase chain reaction( PCR) analysis. ATF-4,phosphorylated PERK and e IF2α protein levels were detected by Western blot assay. RESULTS:: showed that treatment with OPD'( 6 µmol·L-1) significantly increased the rate of apoptosis; expressions of endoplasmic reticulum stress related genes were increased. The morphology of the endoplasmic reticulum was changed. In addition,different concentrations of OPD could partially reverse the myocardial cell injury caused by OPD'. The experimental results showed that OPD'-induced myocardial toxicity may be associated with the endoplasmic reticulum stress,and OPD may modulate the expression of CYP2 J3 to relieve the endoplasmic reticulum stress caused by OPD'.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Espirostanos/farmacologia , Apoptose , Cardiotônicos/farmacologia , Células Cultivadas , Humanos
6.
DNA Cell Biol ; 38(8): 796-807, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31295012

RESUMO

Myocardial hypertrophy is an important cause of heart failure and sudden death. Studies have shown that Mitofusin-2 (MFN2) is downregulated in myocardial hypertrophy, but the upstream regulation mechanism underlying its downexpression in cardiomyocytes is still unclear. This study aims to identify the expression profile of microRNAs (miRNAs) in hypertrophic cardiomyopathy (HCM) and explore the function of miRNA-20 in inducing cardiomyocyte hypertrophy through regulating MFN2. Through miRNA + mRNA microarray analysis, 1451 miRNAs were identified, 367 miRNAs expressed differently between groups. Meanwhile, a number of 24,718 mRNAs were identified, among which 5850 mRNAs were upregulated and 3005 mRNAs were downregulated in HCM group compared with the control group. Expression of hsa-miRNA-20a-5p was 2.26 times higher in the HCM group compared with the control group and 7 target gene prediction programs predicted MFN2 as a target of miRNA-20. In vitro model of hypertrophic cardiomyocytes displayed high expression level of miRNA-20, atrial natriuretic peptide (ANP) mRNA, and protein, accompanying low expression level of Mfn2 mRNA and protein, which meant miRNA-20 played a role in cardiomyocyte hypertrophy and might interact with MFN2 to function. Thereafter, overexpression of miRNA-20 led to cell hypertrophy accompanied with lowly expressed Mfn2 mRNA and protein. When transfected with miRNA-20 inhibitors, the expression of miRNA-20 and ANP gene was attenuated and MFN2 was the other way around. The cell surface area of Ang II group and mimic group was significantly larger compared with the control group, and in the inhibitor+Ang II group, the area was significantly decreased compared with the Ang II group. Dual-luciferase assays showed that miRNA-20 bound to 3' untranslated region of MFN2 and inhibited its expression. In conclusion, hypertrophic myocardium and normal myocardium have different miRNA expression profiles and the effect of miRNA-20 reducing the expression of MFN2 plays a role in promoting cardiomyocyte hypertrophy.


Assuntos
Cardiomiopatia Hipertrófica/genética , GTP Fosfo-Hidrolases/genética , MicroRNAs/genética , Proteínas Mitocondriais/genética , Miócitos Cardíacos/patologia , Regiões 3' não Traduzidas , Adulto , Angiotensina II/farmacologia , Animais , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Miócitos Cardíacos/efeitos dos fármacos , Ratos Wistar
7.
Zhongguo Zhong Yao Za Zhi ; 44(11): 2331-2337, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359660

RESUMO

Astragaloside Ⅳ(AS-Ⅳ) has protective effects against ischemia-reperfusion injury(IRI), but its mechanism of action has not yet been determined. This study aims to investigate the protective effects and mechanism of AS-Ⅳ on H9c2 cardiomyocyte injury induced by hypoxia-reoxygenation(H/R). The H/R model of myocardial cells was established by hypoxic culture for 12 hours and then reoxygenation culture for 8 hours. After AS-Ⅳ treatment, cell viability, the reactive oxygen species(ROS) levels, as well as the content or activity of superoxide dismutase(SOD), malondialdehyde(MDA), interleukin 6(IL-6), and tumor necrosis factor alpha(TNF-α), were measured to evaluate the effect of AS-Ⅳ treatment. The effect of AS-Ⅳ on HO-1 protein expression and nuclear Nrf2 and Bach1 protein expression was determined by Western blot. Finally, siRNA was used to knock down HO-1 gene expression to observe its reversal effect on AS-Ⅳ intervention. The results showed that as compared with the H/R model group, the cell viability was significantly increased(P<0.01), ROS level in the cells, MDA, hs-CRP and TNF-α in cell supernatant and nuclear protein Bach1 expression in the cells were significantly decreased(P<0.01), while SOD content, HO-1 protein expression in cells and expression of nuclear protein Nrf2 were significantly increased(P<0.01) in H/R+AS-Ⅳ group. However, pre-transfection of HO-1 siRNA into H9c2 cells by liposome could partly reverse the above effects of AS-Ⅳ after knocking down the expression of HO-1. This study suggests that AS-Ⅳ has significant protective effect on H/R injury of H9c2 cardiomyocytes, and Nrf2/Bach1/HO-1 signaling pathway may be a key signaling pathway for the effect.


Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Transdução de Sinais , Triterpenos/farmacologia , Apoptose , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Hipóxia Celular , Células Cultivadas , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo
8.
Braz J Med Biol Res ; 52(7): e8732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314855

RESUMO

Inflammation plays an important role in the development of cardiovascular diseases (CVDs), suggesting that the immune system is a target of therapeutic interventions used for treating CVDs. This study evaluated mechanisms underlying inflammatory response and cardiomyocyte hypertrophy associated with bacterial lipopolysaccharide (LPS)- or heat shock protein 60 (HSP60)-induced Toll-like receptor (TLR) stimulation and the effect of a small interfering RNA (siRNA) against Ca2+/calmodulin-dependent kinase II delta B (CaMKIIδB) on these outcomes. Our results showed that treatment with HSP60 or LPS (TLR agonists) induced cardiomyocyte hypertrophy and complement system C3 and factor B gene expression. In vitro silencing of CaMKIIδB prevented complement gene transcription and cardiomyocyte hypertrophy associated with TLR 2/4 activation but did not prevent the increase in interleukin-6 and tumor necrosis factor-alfa gene expression in primary cultured cardiomyocytes. Moreover, CaMKIIδB silencing attenuated nuclear factor-kappa B expression. These findings supported the hypothesis that CaMKIIδB acts as a link between inflammation and cardiac hypertrophy. Furthermore, the present study is the first to show that extracellular HSP60 activated complement gene expression through CaMKIIδB. Our results indicated that a stress stimulus induced by LPS or HSP60 treatment promoted cardiomyocyte hypertrophy and initiated an inflammatory response through the complement system. However, CaMKIIδB silencing prevented the cardiomyocyte hypertrophy independent of inflammatory response induced by LPS or HSP60 treatment.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Miócitos Cardíacos/patologia , Receptores Toll-Like/metabolismo , Animais , Chaperonina 60/farmacologia , Expressão Gênica , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , RNA Interferente Pequeno , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia
9.
Chem Biol Interact ; 309: 108723, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31228469

RESUMO

Ischemic preconditioning and pharmacological preconditioning are common strategies to prevent lethal myocardial injury, especially nutritional preconditioning (NPC). In this study, we investigated the effects of astragaloside IV (Ast), as an NPC agent, on myocardium suffered anoxia/reoxygenation (A/R) injury. Rats received 5 mg/kg Ast daily for 3 weeks by intragastric administration. Then, hearts were harvested and underwent A/R treatment using a Langendorff apparatus. Ast- pretreatment significantly promoted functional recovery of the myocardium, reduced infarct size, and oxidative stress, and decreased the apoptotic index. Similar findings were demonstrated in H9c2 cardiomyocytes that were pretreated with Ast for 24 h. Moreover, Ast-pretreatment significantly upregulated Bcl-2 expression, especially in mitochondria. The effects of Ast treatment against A/R injury were also reflected by increased antioxidant potential, inhibited reactive oxygen species (ROS) burst, increased oxygen consumption rate, maintained mitochondrial membrane potential (MMP), inhibited mitochondrial permeability transition pore (mPTP) opening, and prevented apoptosis. Selective inhibition of Bcl-2 by ABT-737 decreased myocardial injury protection of Ast. Ast-pretreatment resulted in NPC- related effects against A/R, and mitochondria may be the target of a cascade of events elicited by upregulating Bcl-2 expression, promoting translocation of Bcl-2 into mitochondria, maintaining MMP, inhibiting ROS bursts, thereby leading to recovery of mitochondrial respiration, preventing mPTP opening, decreasing cytochrome C release, preventing apoptosis, and ultimately alleviating myocardial injury.


Assuntos
Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Caspase 3/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nitrofenóis/farmacologia , Nitrofenóis/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Superóxido Dismutase/metabolismo
10.
Int J Nanomedicine ; 14: 3669-3678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190818

RESUMO

Background: Electrospun gelatin/polycaprolactone (Gt/PCL) nanofibrous scaffolds loaded with graphene are novel nanomaterials with the uniquely strong property of electrical conductivity, which have been widely investigated for their potential applications in cardiovascular tissue engineering, including in bypass tracts for atrioventricular block. Purpose: Electrospun Gt/PCL/graphene nanofibrous mats were successfully produced. Scanning electron micrography showed that the fibers with graphene were smooth and homogeneous. In vitro, to determine the biocompatibility of the scaffolds, hybrid scaffolds with different fractions of graphene were seeded with neonatal rat ventricular myocytes. In vivo, Gt/PCL scaffolds with different concentrations of graphene were implanted into rats for 4, 8 and 12 weeks. Results: CCK-8 assays and histopathological staining (including DAPI, cTNT, and CX43) indicated that cells grew and survived well on the hybrid scaffolds if the mass fraction of graphene was lower than 0.5%. After implanting into rats for 4, 8 or 12 weeks, there was no gathering of inflammatory cells around the nanomaterials according to the HE staining results. Conclusion: The results indicate that Gt/PCL nanofibrous scaffolds loaded with graphene have favorable electrical conductivity and biological properties and may be suitable scaffolds for use in the treatment of atrioventricular block. These findings alleviate safety concerns and provide novel insights into the potential applications of Gt/PCL loaded with graphene, offering a solid foundation for comprehensive in vivo studies.


Assuntos
Gelatina/toxicidade , Grafite/toxicidade , Nanofibras/toxicidade , Poliésteres/toxicidade , Engenharia Tecidual , Tecidos Suporte/química , Testes de Toxicidade , Animais , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Suínos
11.
Planta Med ; 85(9-10): 738-744, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185502

RESUMO

Chronic heart failure is the terminal stage of various cardiovascular diseases. Despite the availability of several classes of drugs, there is still an unmet need for effective treatment. Based on bench work during the past two decades, we have proposed that enhancement of ß 2-adrenergic receptor signaling in combination with the presently preferred ß 1-adrenergic receptor blockade would be a promising strategy. Chinese herbal medicines have been shown to be effective in the treatment of heart failure, although the mechanisms largely remain unknown. In the present study, we screened an herbal medicine compound/extract library for ß-adrenergic receptor ligands to determine the target of certain effective botanical remedies and seek a leading compound(s) for chronic heart failure treatment. Using a high-throughput screening assay, we identified higenamine, which has a long history in chronic heart failure treatment in traditional Chinese medicine, to be a potent ß-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both ß 1-adrenergic receptor and ß 2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a ß 2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine. In conclusion, we found an herbal compound, higenamine, to be a dual agonist for ß 1/ß 2-adrenergic receptors with no preference in stimulating the Gs and Gi pathways in ß 2-adrenergic receptor signaling. Our results elucidated not only the target of higenamine to explain its pharmacological effect in treating chronic heart failure, but also the mechanisms of its cardiac toxicity.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Alcaloides/farmacologia , Medicamentos de Ervas Chinesas/química , Ensaios de Triagem em Larga Escala/métodos , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Tetra-Hidroisoquinolinas/química
12.
Toxicol Lett ; 313: 77-90, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220554

RESUMO

Quetiapine is a common atypical antipsychotic used to treat mental disorders such as schizophrenia, bipolar disorder, and major depressive disorder. There has been increasing number of reports describing its cardiotoxicity. However, the molecular mechanisms underlying quetiapine-induced myocardial injury remain largely unknown. Herein, we reported a novel cell death type, quetiapine-induced necroptosis, which accounted for quetiapine cardiotoxicity in mice and proposed novel therapeutic strategies. Quetiapine-treated hearts showed inflammatory infiltration and evident fibrosis after 21-day continuous injection. The specific increases of protein levels of RIP3, MLKL and the phosphorylation of MLKL showed that quetiapine induced necroptotic cell death both in vivo and in vitro. Pharmacologic blockade of necroptosis using its specific inhibitor Necrostatin-1 attenuated quetiapine-induced myocardial injury in mice. In addition, quetiapine imbalanced the endocannabinoid system and caused opposing effects on two cannabinoid receptors (CB1R and CB2R). Specific antagonists of CB1R (AM 281, Rimonabant), but not its agonist ACEA significantly ameliorated the heart histopathology induced by chronic quetiapine exposure. By contrast, specific agonists of CB2R (JWH-133, AM 1241), but not its antagonist AM 630 exerted beneficial roles against quetiapine cardiotoxicity. The protective agents (AM 281, Rimonabant, AM 1241, and JWH-133) consistently inactivated the quetiapine-induced necroptosis signaling. Quetiapine bidirectionally regulates cannabinoid receptors and induces myocardial necroptosis, leading to cardiac toxic effects. Therefore, pharmacologic inhibition of CB1R or activation of CB2R represents promising therapeutic strategies against quetiapine-induced cardiotoxicity.


Assuntos
Antipsicóticos/toxicidade , Apoptose/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/toxicidade , Antagonistas de Receptores de Canabinoides/toxicidade , Cardiomiopatias/induzido quimicamente , Miócitos Cardíacos/efeitos dos fármacos , Fumarato de Quetiapina/toxicidade , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiotoxicidade , Linhagem Celular , Endocanabinoides/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Necrose , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Cell Physiol Biochem ; 53(1): 36-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169990

RESUMO

BACKGROUND/AIMS: Ivabradine lowers the heart rate by inhibition of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels mediating the 'funny' pacemaker current If in the sinoatrial node. It is clinically approved for the treatment of heart failure and angina pectoris. Due to its proposed high selectivity for If administration of ivabradine is not associated with the side effects commonly observed following the application of other heart rate lowering agents. Recent evidence, however, has shown significant affinity of ivabradine towards Kv11.1 (ether-a-go-go related gene, ERG) potassium channels. Despite the inhibition of Kv11.1 channels by ivabradine, cardiac action potential (AP) duration and heart rate corrected QT interval (QTc) of the human electrocardiogram (ECG) were not prolonged. We thus surmised that compensatory mechanisms might counteract the drug's inhibitory action on Kv11.1. METHODS: The effects of ivabradine on human Kv11.1 and Kv7.1 potassium, Cav1.2 calcium, and Nav1.5 sodium channels, heterologously expressed in tsA-201 cells, were studied in the voltage-clamp mode of the whole cell patch clamp technique. In addition, changes in action potential parameters of human induced pluripotent stem cell (iPSC) derived cardiomyocytes upon application of ivabradine were studied with current-clamp experiments. RESULTS: Here we show that ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Nav1.5 sodium channels at therapeutically relevant concentrations. Within this study we also confirm recent findings of human Kv11.1 inhibition by low µM concentrations of ivabradine and observed no prolongation of ventricular-like APs in cardiomyocytes derived from iPSCs. CONCLUSION: Our results provide an explanation why ivabradine, despite its affinity for Kv11.1 channels, does not prolong the cardiac AP and QTc interval. Furthermore, our results suggest the inhibition of voltage-gated Nav1.5 sodium channels to underlie the recent observations of slowed atrioventricular conduction by increased atrial-His bundle intervals upon administration of ivabradine.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Canais Iônicos/metabolismo , Ivabradina/farmacologia , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Linhagem Celular , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Canais Iônicos/antagonistas & inibidores , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp
14.
Ecotoxicol Environ Saf ; 179: 249-256, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31054378

RESUMO

The functional role of 1,25-vitamin D3 in cooking oil fumes (COFs)-derived PM2.5-induced cell damage is largely unexplored. The present study investigated the protective role of 1,25-vitamin D3 against cell injury by possible involvement of JAK/STAT and NF-κB signaling pathways in cardiomyocytes. Cell viability was measured using CCK-8 assay, and cell apoptosis was analyzed by flow cytometry, qRT-PCR and Western blot in cultured rat neonatal cardiomyocytes treated with 1,25-vitamin D3 and COFs-derived PM2.5. Expressions of JAK/STAT and NF-κB signaling pathway were measured by Western blot. The results suggested that treatment with COFs-derived PM2.5 significantly decreased cell viability and increased apoptosis and oxidative stress in cultured rat neonatal cardiomyocytes. 1,25-vitamin D3 pretreatment alleviated the cell injury by increasing cell viability and decreasing apoptosis in the cardiomyocytes. 1,25-vitamin D3 pretreatment also decreased the ROS level and inflammation in the cardiomyocytes. Furthermore, 1,25-vitamin D3 pretreatment alleviated COFs-derived PM2.5-evoked elevation of JAK/STAT and NF-κB signaling pathways. Our study showed that 1,25-vitamin D3 pretreatment protected cardiomyocytes from COFs-derived PM2.5-induced injury by decreasing ROS, apoptosis and inflammation level via activations of the JAK/STAT and NF-κB signaling pathways.


Assuntos
Poluentes Atmosféricos/toxicidade , Anti-Inflamatórios/farmacologia , Colecalciferol/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Culinária/métodos , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Ratos , Transdução de Sinais/efeitos dos fármacos
15.
Zhongguo Zhong Yao Za Zhi ; 44(8): 1642-1647, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090329

RESUMO

This paper was aimed to investigate the inhibitory effect of aconitine(AC) on angiotensin Ⅱ(Ang Ⅱ)-induced H9 c2 cell hypertrophy and explore its mechanism of action. The model of hypertrophy was induced by Ang Ⅱ(1×10-6 mol·L-1),and cardiomyocytes were incubated with different concentrations of AC. Western blot was used to quantify the protein expression levels of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),ß-myosin heavy chain(ß-MHC),and α-smooth muscle actin(α-SMA). Real-time quantitative PCR(qRT-PCR) was used to quantify the mRNA expression levels of cardiac hypertrophic markers ANP,BNP and ß-MHC. In addition,the fluorescence intensity of the F-actin marker,an important component of myofibrils,was detected by using laser confocal microscope. AC could significantly reverse the increase of total protein content in H9 c2 cells induced by Ang Ⅱ; qRT-PCR results showed that AC could significantly inhibit the ANP,BNP and ß-MHC mRNA up-regulation induced by AngⅡ. Western blot results showed that AC could significantly inhibit the ANP,BNP and ß-MHC protein up-regulation induced by AngⅡ. In addition,F-actin expression induced by Ang Ⅱ could be inhibited by AC,and multiple indicators of cardiomyocyte hypertrophy induced by Ang Ⅱ could be down-regulated,indicating that AC may inhibit cardiac hypertrophy by inhibiting the expression of hypertrophic factors,providing new clues for exploring the cardiovascular protection of AC.


Assuntos
Aconitina/farmacologia , Angiotensina II , Miócitos Cardíacos/efeitos dos fármacos , Actinas/metabolismo , Fator Natriurético Atrial/metabolismo , Miosinas Cardíacas/metabolismo , Cardiomegalia , Células Cultivadas , Humanos , Hipertrofia , Cadeias Pesadas de Miosina/metabolismo , Peptídeo Natriurético Encefálico/metabolismo
16.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052520

RESUMO

Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK Thr 188 phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.


Assuntos
Cardiomegalia/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Algoritmos , Cardiomegalia/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Cardiovasculares , Terapia de Alvo Molecular/métodos , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos
17.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071921

RESUMO

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates ß-adrenergic receptor (ß-AR) signaling and ultimately limits ß-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to ß-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates ß-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.


Assuntos
Cardiomiopatias/genética , Insuficiência Cardíaca/genética , Receptores CXCR4/genética , Animais , Fator Natriurético Atrial/genética , Cardiomiopatias/fisiopatologia , Quimiocina CXCL12/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Isoproterenol/administração & dosagem , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Receptores Adrenérgicos beta/genética , Transdução de Sinais/genética
18.
Biomed Res Int ; 2019: 9786101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080837

RESUMO

Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Uncoupling protein 2 (UCP2) involves immune response, regulation of oxidative stress, and maintenance of mitochondrial membrane potential as well as energy production. However, whether and how UCP2 plays roles in the development of septic cardiac dysfunction are largely unknown. Here, intraperitoneal injection of LPS significantly activated UCP2 expression accompanied by a significant decrease of cardiac function and caused a significantly lower survival rate in mice. Of note, knockdown of UCP2 through a cardiotropic adenoassociated viral vector carrying a short hairpin RNA (shRNA) specifically targeting the UCP2 evoked resistance to LPS-triggered septic cardiac dysfunction and lethality in vivo. Moreover, UCP2 deficiency ameliorated the reduced levels of intracellular ATP in the LPS-challenged heart tissues and preserved mitochondrial membrane potential loss in primary adult mouse cardiomyocytes in LPS-challenged animals. Mechanistically, we confirmed that the inhibition of UCP2 promoted autophagy in response to LPS, as shown by an increase in LC3II and a decrease in p62. At last, the autophagy inhibitor 3-MA abolished UCP2 knockdown-afforded cardioprotective effects. Those results indicate that UCP2 drives septic cardiac dysfunction and that the targeted induction of UCP2-mediated autophagy may have important therapeutic potential.


Assuntos
Cardiomiopatias/metabolismo , Choque Séptico/metabolismo , Proteína Desacopladora 2/imunologia , Proteína Desacopladora 2/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Autofagia/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Modelos Animais , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , RNA Interferente Pequeno , Espécies Reativas de Oxigênio/metabolismo , Sepse/metabolismo , Taxa de Sobrevida , Fatores de Transcrição , Proteína Desacopladora 2/genética
19.
Int Heart J ; 60(3): 728-735, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31105148

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-ß1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of ß-hydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.


Assuntos
Compostos Benzidrílicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Animais , Compostos Benzidrílicos/efeitos adversos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Fibrose/tratamento farmacológico , Glucosídeos/efeitos adversos , Interleucina-6/metabolismo , Cetonas/metabolismo , Masculino , Modelos Animais , Peptídeos Natriuréticos/metabolismo , Ratos , Ratos Endogâmicos Dahl , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
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