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1.
Wiad Lek ; 74(2): 247-251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33813480

RESUMO

OBJECTIVE: The aim: Is to study the morphological features of rats' hearts after prenatal administration of glucocorticoids. PATIENTS AND METHODS: Materials and methods: In this study we used histological, immunohistochemical, electron-microscopic and statistical research methods. RESULTS: Results: It is found that at 30th day after birth in rats after intrafetal introduction of dexamethasone in myocardium a relative area occupied by arterial vessels is significantly smaller in comparison with control. Absolute and relative number of Ki-67+-cardiomyocytes in the myocardium of experimental rats is reduced throughout the second week after birth and is significantly less compared to the control group. In the nuclei of cardiomyocytes of experimental rats is rendered the greater amount of heterochromatin in comparison with cardiomyocytes of the control group where euchromatin prevails. CONCLUSION: Conclusions: After intrafetal injection of dexametazone changes in dynamics and significantly smaller index of relative area occupied by arterial vessels in ventricular myocardium at the 30th day after birth are observed; the absolute and relative number of Ki-67+ -cardiomyocytes in myocardium decreases during the second week after birth and is significantly lower compared to the control group; in the nuclei of cardiomyocytes of experimental rats a greater amount of heterochromatin is visualized, and in cardiomyocytes of the control group - euchromatin.


Assuntos
Miocárdio , Miócitos Cardíacos , Dexametasona , Feminino , Glucocorticoides , Ventrículos do Coração , Humanos , Gravidez
2.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33804922

RESUMO

Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with T. cruzi and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFß1) and T. cruzi stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of T. cruzi-infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC.


Assuntos
Cardiomiopatia Chagásica/terapia , MicroRNAs/genética , Terapêutica com RNAi/métodos , Animais , Células Cultivadas , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Colágeno/genética , Colágeno/metabolismo , Fibrose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Miofibroblastos/metabolismo , Regulação para Cima
3.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809279

RESUMO

Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc. In vitro, sildenafil dose-dependently reduced CXCL10 release by activated myocytes and impaired cytokine-induced Signal transducer and activator of transcription 1 (STAT1), Nuclear factor-κB (NFκB) and c-Jun N-terminal kinase (JNK) phosphorylation. This was also seen in cardiomyocytes. Sildenafil-induced CXCL10 inhibition at the systemic and human muscle cell level supports the hypothesis that PDE5i could be a potential therapeutic therapy to prevent and treat muscle damage in SSc.


Assuntos
Quimiocina CXCL10/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Cardiomiopatias Diabéticas/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Citrato de Sildenafila/farmacologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/patologia , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B , Inibidores da Fosfodiesterase 5/farmacologia , Fator de Transcrição STAT1/genética , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia
4.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810249

RESUMO

Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca2+-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunoblotting studies on isolated atrial and ventricular cardiac myocytes and surfaces, as well as on pseudo- and intracardiac ECGs, either in vivo or in Langendorff-perfused explanted mouse hearts. We observed that TRPM4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in myocytes. Hearts from Trpm4-/- mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na+ current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na+ current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Nav1.5 function in murine cardiac myocytes.


Assuntos
Arritmias Cardíacas/genética , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Canais de Cátion TRPM/metabolismo , Potenciais de Ação , Animais , Células Cultivadas , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/fisiologia , Canais de Cátion TRPM/genética , Função Ventricular
5.
Proc Natl Acad Sci U S A ; 118(16)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33811184

RESUMO

Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2-infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OAS-RNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.


Assuntos
Células Epiteliais/imunologia , Células Epiteliais/virologia , Imunidade Inata , Pulmão/patologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/virologia , RNA de Cadeia Dupla/metabolismo , /imunologia , Células A549 , Endorribonucleases/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Nariz/virologia , Replicação Viral , eIF-2 Quinase
6.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(2): 222-228, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33829695

RESUMO

Objective: The purpose of this study was to investigate the protective effect of astragaloside Ⅳ (AS-Ⅳ) on neonatal rats' hypoxic/reoxygenated (H/R) injured myocardial cells and to explore its underlying mechanism. Methods: Cardiac cells were extracted from newborn rats and divided into control, H/R, H/R-low AS-Ⅳ (0.1 µmol/L AS-Ⅳ), H/R-medium AS-Ⅳ (1 µmol/L AS-Ⅳ), H/R-high AS-Ⅳ (10 µmol/L AS-Ⅳ) and H/R-high AS-Ⅳ-AKT (10 µmol/L AS-Ⅳ+5 µmol/L AKT) groups. After 48 h of treatment, the contents of LC3-Ⅱ, p62, AKT, pAKT, rapamycin (mTOR) mammalian targets and uncoordinated 51-like kinase 1 (ULK1) in cardiac myocytes were compared. Immunofluorescence staining was used to detect the expression of P62 in myocardium autophagosome. Restults: AS-Ⅳ improved the proliferative activity of cardio AS-Ⅳ improved the proliferative activity of cardiomyocytes in H/R injury in a dose-dependent manner and inhibited the level of cell autophagy. However, when AKT inhibitors were added, the effect of AS-Ⅳ was partially inhibited ( P<0.05). Gene and protein expression showed that AS-Ⅳ had no significant effect on the expression of AKT and mTOR genes ( P>0.05), but could significantly promote the phosphorylation of AKT and mTOR ( P<0.05). Immunofluorescence staining results showed that high concentrations of the AS - Ⅳ can reverse H/R injury induced the expression of autophagy body P62. Conclusion: AS-Ⅳ showed protection effect on H/R injured myocardial cells. The possible mechanism is by reducing the autophagy level via activating the mTOR signal in the PI3K/AKT pathway, thereby preventing H/R damage in neonatal rat cardiomyocytes.


Assuntos
Infarto do Miocárdio , Fosfatidilinositol 3-Quinases , Animais , Apoptose , Autofagia , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Saponinas , Transdução de Sinais , Triterpenos
7.
Science ; 372(6538): 201-205, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33833125

RESUMO

Cardiac regeneration requires dedifferentiation and proliferation of mature cardiomyocytes, but the mechanisms underlying this plasticity remain unclear. Here, we identify a potent cardiomyogenic role for Krüppel-like factor 1 (Klf1/Eklf), which is induced in adult zebrafish myocardium upon injury. Myocardial inhibition of Klf1 function does not affect heart development, but it severely impairs regeneration. Transient Klf1 activation is sufficient to expand mature myocardium in uninjured hearts. Klf1 directs epigenetic reprogramming of the cardiac transcription factor network, permitting coordinated cardiomyocyte dedifferentiation and proliferation. Myocardial expansion is supported by Klf1-induced rewiring of mitochondrial metabolism from oxidative respiration to anabolic pathways. Our findings establish Klf1 as a core transcriptional regulator of cardiomyocyte renewal in adult zebrafish hearts.


Assuntos
Reprogramação Celular , Coração/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Miócitos Cardíacos/fisiologia , Regeneração , Proteínas de Peixe-Zebra/metabolismo , Animais , Cardiomegalia Induzida por Exercícios , Desdiferenciação Celular , Diferenciação Celular , Proliferação de Células , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Glicólise , Coração/embriologia , Ventrículos do Coração/citologia , Fatores de Transcrição Kruppel-Like/genética , Desenvolvimento Muscular , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Via de Pentose Fosfato , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
8.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802229

RESUMO

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias.


Assuntos
Síndrome de Brugada/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo , Síndrome de Brugada/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Miócitos Cardíacos/patologia
9.
Circ Res ; 128(8): 1214-1236, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33856918

RESUMO

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.


Assuntos
/metabolismo , Doenças Cardiovasculares/virologia , Miócitos Cardíacos/virologia , Internalização do Vírus , Biomarcadores/metabolismo , /epidemiologia , Cardiomiopatias/virologia , Expressão Gênica , Humanos , Sistema Imunitário/fisiologia , Miocárdio/enzimologia , Miócitos Cardíacos/enzimologia , Neuropilina-1/metabolismo , Ativação Plaquetária , RNA Mensageiro/metabolismo , Sistema Renina-Angiotensina/fisiologia , Volta ao Esporte , Fatores de Risco , Glicoproteína da Espícula de Coronavírus/metabolismo , Troponina/metabolismo , Remodelação Ventricular , Ligação Viral , Internalização do Vírus/efeitos dos fármacos
10.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809429

RESUMO

The regenerative capacity of cardiomyocytes is insufficient to functionally recover damaged tissue, and as such, ischaemic heart disease forms the largest proportion of cardiovascular associated deaths. Human-induced pluripotent stem cells (hiPSCs) have enormous potential for developing patient specific cardiomyocytes for modelling heart disease, patient-based cardiac toxicity testing and potentially replacement therapy. However, traditional protocols for hiPSC-derived cardiomyocytes yield mixed populations of atrial, ventricular and nodal-like cells with immature cardiac properties. New insights gleaned from embryonic heart development have progressed the precise production of subtype-specific hiPSC-derived cardiomyocytes; however, their physiological immaturity severely limits their utility as model systems and their use for drug screening and cell therapy. The long-entrenched challenges in this field are being addressed by innovative bioengingeering technologies that incorporate biophysical, biochemical and more recently biomimetic electrical cues, with the latter having the potential to be used to both direct hiPSC differentiation and augment maturation and the function of derived cardiomyocytes and cardiac tissues by mimicking endogenous electric fields.


Assuntos
Coração/fisiologia , Miócitos Cardíacos/citologia , Células-Tronco Pluripotentes/citologia , Animais , Bioengenharia , Diferenciação Celular , Estimulação Elétrica , Humanos
11.
Sheng Li Xue Bao ; 73(2): 275-285, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33903889

RESUMO

This study aimed to explore the positive inotropic effect of phosphodiesterase type 9 (PDE9) inhibitor PF-04449613 in ratsand its cellular and molecular mechanisms. The heart pressure-volume loop (P-V loop) analysis was used to detect the effects of PF-04449613 on rat left ventricular pressure-volume relationship, aortic pressures and peripheral vessel resistance in healthy rats. The Langendorff perfusion of isolated rat heart was used to explore the effects of PF-04449613 on heart contractility. The cardiomyocyte sarcoplasmic reticulum (SR) Ca2+ transients induced by field stimulation and caffeine were used to analyze the mechanism underlying the effect of PF-04449613 using Fluo-4 AM as a Ca2+ indicator. The results indicated as follows: (1) PF-04449613 (5.5 mg/kg, ip) significantly increased the stroke work, cardiac output, stroke volume, end-systolic pressure and ejection fraction (P < 0.05), and decreased the end-systolic volume, end-diastolic volume and end-diastolic pressure (P < 0.05). Meanwhile, the systolic blood pressure was increased and diastolic blood pressure and arterial elastance were decreased after PF-04449613 treatment (P < 0.05). (2) PF-04449613 (0.001, 0.01, 0.1, 1 µmol/L) significantly increased the left ventricular developed pressure (LVDP) in a concentration-dependent manner in vitro (P < 0.05). (3) PF-04449613 (5 µmol/L) significantly increased the amplitude of SR Ca2+ transients mediated by facilitating sarcoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) (P < 0.05). (4) PF-04449613 (5 µmol/L) decreased the SR Ca2+ leak rate via ryanodine receptor 2 (RyR2) (P < 0.05). In conclusion, PF-04449613 exerted positive inotropic effect both in vivo and in vitro by enhancing SERCA2a activity.


Assuntos
Cálcio , Inibidores de Fosfodiesterase , Animais , Cálcio/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Diester Fosfórico Hidrolases , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina , Retículo Sarcoplasmático
12.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808720

RESUMO

Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 106 cells each) can be fully replicated by a single combined dose of 3 × 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 106) and vehicle × 2; or (3) three doses of CPCs (1 × 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (p < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (-32.7%, 182.6 ± 15.1 µm2 vs. 271.5 ± 27.2 µm2, p < 0.05, in the risk region and -28.5%, 148.5 ± 12.1 µm2 vs. 207.6 ± 20.5 µm2, p < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.


Assuntos
Cardiomiopatias/etiologia , Dosagem de Genes , Isquemia Miocárdica/complicações , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Biomarcadores , Biópsia , Pesos e Medidas Corporais , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Cardiomiopatias/terapia , Células Cultivadas , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Testes de Função Cardíaca , Hemodinâmica , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Camundongos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/etiologia , Proteínas Proto-Oncogênicas c-kit/metabolismo
13.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806909

RESUMO

Kirenol (KRL) is a biologically active substance extracted from Herba Siegesbeckiae. This natural type of diterpenoid has been widely adopted for its important anti-inflammatory and anti-rheumatic properties. Despite several studies claiming the benefits of KRL, its cardiac effects have not yet been clarified. Cardiotoxicity remains a key concern associated with the long-term administration of doxorubicin (DOX). The generation of reactive oxygen species (ROS) causes oxidative stress, significantly contributing to DOX-induced cardiac damage. The purpose of the current study is to investigate the cardio-protective effects of KRL against apoptosis in H9c2 cells induced by DOX. The analysis of cellular apoptosis was performed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining assay and measuring the modulation in the expression levels of proteins involved in apoptosis and Nrf2 signaling, the oxidative stress markers. Furthermore, Western blotting was used to determine cell survival. KRL treatment, with Nrf2 upregulation and activation, accompanied by activation of PI3K/AKT, could prevent the administration of DOX to induce cardiac oxidative stress, remodeling, and other effects. Additionally, the diterpenoid enhanced the activation of Bcl2 and Bcl-xL, while suppressing apoptosis marker proteins. As a result, KRL is considered a potential agent against hypertrophy resulting from cardiac deterioration. The study results show that KRL not only activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling pathway, but also suppresses caspase-dependent apoptosis.


Assuntos
Cardiotônicos/farmacologia , Diterpenos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Diterpenos/química , Doxorrubicina/efeitos adversos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeos Natriuréticos/metabolismo , Fosforilação , Transporte Proteico
14.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33807107

RESUMO

During the postnatal period, mammalian cardiomyocytes undergo numerous maturational changes associated with increased cardiac function and output, including hypertrophic growth, cell cycle exit, sarcomeric protein isoform switching, and mitochondrial maturation. These changes come at the expense of loss of regenerative capacity of the heart, contributing to heart failure after cardiac injury in adults. While most studies focus on the transcriptional regulation of embryonic or adult cardiomyocytes, the transcriptional changes that occur during the postnatal period are relatively unknown. In this review, we focus on the transcriptional regulators responsible for these aspects of cardiomyocyte maturation during the postnatal period in mammals. By specifically highlighting this transitional period, we draw attention to critical processes in cardiomyocyte maturation with potential therapeutic implications in cardiovascular disease.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Regeneração/genética , Transcrição Genética , Animais , Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células , Montagem e Desmontagem da Cromatina , Metabolismo Energético , Epigênese Genética , Humanos , Hipertrofia , Oxirredução
15.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33810024

RESUMO

Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.


Assuntos
Precondicionamento Isquêmico Miocárdico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Morte Celular/efeitos dos fármacos , Humanos , Precondicionamento Isquêmico Miocárdico/métodos , Dinâmica Mitocondrial/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Regeneração , Transdução de Sinais/efeitos dos fármacos , Pesquisa Médica Translacional
16.
Arq Bras Cardiol ; 116(2): 315-322, 2021 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33656082

RESUMO

BACKGROUND: Doxorubicin is associated with cardiotoxicity and late cardiac morbidity. Heme is related to cellular oxidative stress. However, its specific regulation in cardiomyocytes under doxorubicin effects has not yet been documented. OBJECTIVE: This study seeks to evaluate the changing profiles of rate-limiting enzymes in the heme metabolism pathway under the effect of doxorubicin. METHODS: H9c2 cardiomyocytes were incubated with doxorubicin at different concentrations (1,2,5,10µM respectively). The real-time PCR and Western Blot were used to determine the mRNA and protein expression for four pivotal enzymes (ALAS1, ALAS2, HOX-1, and HOX-2) regulating cellular heme metabolism, as well as the levels of heme were detected by ELISA. p<0.01 was considered significant. RESULTS: This study observed a dose-dependent changing pattern in heme levels in H9c2 cells with the highest level at the 5µM concentration for doxorubicin, which occurred synchronously with the highest upregulation level of ALAS1, as well as the degradative enzymes, HOX-1, and HOX-2 in mRNA and protein expression. By contrast, ALAS2, contrary to the increasing concentrations of doxorubicin, was found to be progressively down-regulated. CONCLUSION: The increase in ALAS1 expression may play a potential role in the heme level elevation when H9c2 cardiomyocyte was exposed to doxorubicin and may be a potential therapeutic target for doxorubicin-induced myocardial toxicity. (Arq Bras Cardiol. 2021; 116(2):315-322).


Assuntos
Doxorrubicina , Miócitos Cardíacos , 5-Aminolevulinato Sintetase/metabolismo , Cardiotoxicidade , Heme/metabolismo , Humanos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
18.
Adv Clin Exp Med ; 30(3): 255-261, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33768740

RESUMO

BACKGROUND: Puerarin demonstrates a protective effect in many cardiovascular diseases. However, the role of puerarin in acute myocardial infarction (AMI)-induced injury and the exact molecular mechanisms are not fully understood. OBJECTIVES: To investigate whether puerarin pretreatment improves cardiac function and to study the mechanism of action of puerarin. MATERIAL AND METHODS: Thirty rats were grouped into sham group, AMI group and AMI+puerarin (PUE) group at random (n = 10 per group). Except for the sham group, a model of AMI was established via left anterior descending artery ligation. The PUE group received puerarin 120 mg/(kg × day) for 7 days before the operation. Echocardiography was used for evaluation of cardiac function in rats and TUNEL staining for measuring myocardial apoptosis. The expression levels of p-PI3K, t-Akt, p-Akt, Bax, Bcl-2, and cleaved caspase-3 proteins were measured with western blot. RESULTS: Compared to the sham group, the AMI group demonstrated poor cardiac function and decreased p-PI3K, p-Akt and Bcl-2 proteins levels, while Bax, cleaved caspase-3, and myocardial apoptosis levels increased. Compared with the AMI group, the PUE group showed significant improvement in cardiac function and increased protein expression of p-PI3K, p-Akt and Bcl-2, while Bax and cleaved caspase-3 levels decreased and myocardial apoptosis was attenuated. CONCLUSIONS: Puerarin pretreatment in AMI can effectively improve cardiac function by inhibiting myocardial apoptosis. The molecular mechanism of this protective effect may be mediated by activating the PI3K/Akt pathway in cardiomyocytes.


Assuntos
Infarto do Miocárdio , Fosfatidilinositol 3-Quinases , Animais , Apoptose , Isoflavonas , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
19.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1345-1356, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33787131

RESUMO

Myocardial ischemia-reperfusion injury(MIRI) is an urgent problem in clinical treatment. As cardiomyocytes are terminal cells, MIRI-induced cardiomyocyte death will irreversibly damage the structure and function of the heart. In previous studies, apoptosis was considered to be the only way to regulate cell death, while necrosis could not be regulated. However, current studies have shown that cell necrosis could also be regulated, which was collectively called programmed cell death(PCD). Regulated cell death is actively mediated through molecular pathways, so there is the possibility of inhibiting this signaling to reduce MIRI. At present, PCD mainly includes apoptosis, autophagy, necrosis, pyroptosis and ferroptosis. As a unique treature in China, traditional Chinese medicine has the advantages of multiple pathways, multiple targets, low toxicity, less side effects and low economic costs. With the in-depth study of the efficacy of traditional Chinese medicine against MIRI, it has been confirmed that traditional Chinese medicine could regulate PCD to reduce MIRI. Therefore, this paper focuses on the relationship between PCD and MIRI, and new studies on intervention with relevant traditional Chinese medicine, with the aim to provide new MIRI prevention and treatment methods from the perspective of "intervention of PCD".


Assuntos
Traumatismo por Reperfusão Miocárdica , Apoptose , China , Humanos , Medicina Tradicional Chinesa , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos
20.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1460-1466, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33787144

RESUMO

This project aimed to explore the protective effect of ginsenoside Rg_1 on hypoxia/reoxygenation(H/R)-induced H9 c2 cardiomyocyte injury and its underlying signaling pathway. The H/R model of H9 c2 cardiomyocytes was established and then the cells were divided into different treatment groups. CCK-8(cell counting kit-8) was used to detect the activity of cardiomyocytes; Brdu assay was used to detect the proliferation of H9 c2 cells; the caspase-3 activity was tested, and then the protein expression was assessed by Western blot. Flow cytometry was used to evaluate the apoptosis level of cardiomyocytes. Ginsenoside Rg_1 inhibited H/R-induced cardiomyocyte apoptosis and caspase-3 activity, promoted nuclear transcription of nuclear factor erythroid-2 related factor 2(Nrf2), and enhanced the expression of the downstream heme oxygenase-1(HO-1). Ginsenoside Rg_1 could increase Nrf2 nuclear transcription and HO-1 expression with the increase of concentration(10, 20, 40, 60 µmol·L~(-1)). However, the protective effect of ginsenoside Rg_1 on cardiomyocytes was significantly weakened after the transfection of Nrf2-siRNA. Ginsenoside Rg_1 could protect cardiomyocytes by activating the Nrf2/HO-1 pathway.


Assuntos
Ginsenosídeos , Apoptose , Ginsenosídeos/farmacologia , Heme Oxigenase-1/genética , Humanos , Hipóxia , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2/genética
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