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1.
Rev Assoc Med Bras (1992) ; 67(3): 418-425, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34468608

RESUMO

OBJECTIVE: The aim of this study is to evaluate the myocardium structure in patients with chest pain who were determined to have moderate and/or high risk for cardiac ischemic heart disease (IHD) but who had normal findings on conventional coronary angiography by using native cardiac magnetic resonance imaging (CMRI) T1 mapping and comparing with healthy volunteers. METHODS: A total of 50 patients and 30 healthy volunteers who underwent CMRI were included in our prospective study. Patients whose clinical findings were compatible with stable angina pectoris, with moderate and/or high risk for IHD, but whose conventional coronary angiography was normal, were our patient group. Native T1 values were measured for 17 myocardial segments (segmented based on American Heart Association recommendations) by two radiologists independently. The data obtained were statistically compared with the sample t-test. RESULTS: Myocardial native T1 values were found to be significantly prolonged in the patient group compared with the control group (p<0.05). Inter-observer reliability for native T1 value measurements of groups was high for both patient and control groups (α = 0.92 for the patient group and 0.96 for the control group). CONCLUSION: Findings suggestive of ischemia were detected by T1 mapping in the myocardium of our patients. For this reason, it is recommended that this patient group should be included in early diagnosis and close follow-up assessments for IHD.


Assuntos
Imagem Cinética por Ressonância Magnética , Miocárdio , Angiografia Coronária , Humanos , Isquemia , Estudos Prospectivos , Reprodutibilidade dos Testes , Estados Unidos
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(4): 380-384, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34374257

RESUMO

Objective: To investigate the effects of Shaosha-7 in rats with myocardial ischemia-reperfusion injury and its mechanisms. Methods: male SD rats were divided into sham operation group (n=10), myocardial ischemia-reperfusion injury group (n=10), low, medium and high dose of Shaosha-7 groups (n=10), and positive drug group (n=10). The rats of Shaosha-7 (low, medium and high dose) groups were treated with Shaosha-7 at the doses of 0.4, 0.8 and 1.6 g/kg respectively, once a day for 15 days. The rats of positive drug group were treated with 0.3 g/kg Danshen, once a day for 15 days. The rats of the sham operation group and myocardial ischemia-reperfusion injury were treated with 2 ml/100 g distilled water, once a day for 15 days. After 15 days, the rats of the model group and the treatment group underwent thoracotomy and ligation of coronary artery for 30 minutes, then thoracic cavity was closed after reperfusion. Rats in six groups were executed electrocardiographic examination and their hearts were taken for Hematoxylin-Eosin (HE) staining and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining to observe infarct area and myocardial pathological changes. The contents of cTnI, CK-MB, LDH, MDA, SOD, GSH-Px, TNF-α, IL-18, IL-6 and IL-1 ß in serum were detected by ELISA. The expression of NF-кB was detected by immunohistochemistry. Results: Compared with the sham operation group, the infarct size, the levels of cTnI, CK-MB, CK-MB, LDH, MDA, GSH-Px, TNF-α, IL-18, IL-6, IL-1ß and NF-кB were increased and the content of SOD were decreased in rats with myocardial ischemia-reperfusion injury. Compared with the rats with myocardial ischemia-reperfusion injury, Shaosha-7 improved the arrhythmia and pathological changes, reduced the infarct area, decreased the contents of cTnI, CK-MB, LDH, MDA, GSH-Px, TNF-α, IL-18, IL-6, IL-1 ß, increased the content of SOD, decreased the expression of NF-кB. Conclusion: Mongolian medicine Shaosha-7 can effectively alleviate myocardial ischemia-reperfusion injury in rats. This study provides a theoretical basis for the treatment of myocardial ischemia-reperfusion (I/R) injury with Shaosha-7.


Assuntos
Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Animais , Masculino , Medicina Tradicional da Mongólia , Isquemia Miocárdica/tratamento farmacológico , Miocárdio , NF-kappa B , Ratos , Ratos Sprague-Dawley
3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(4): 439-444, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34374267

RESUMO

Objective: The present study was to determine the effects of aerobic interval training (AIT) on the expressions of SIRT1, Nox4 and inflammatory factor in the heart of rats with myocardial infarction (MI). Methods: Male Sprague Dawley rats were randomly divided into sham-operated group (C), sedentary MI group (MI) and MI with AIT group (ME) (n=10). The MI model was established by ligation the left anterior descending coronary artery. Rats in C groups were subjected to the same surgery, but only threaded and not ligated. After surgery 1 week, rats in ME groups took adaptability training for 1 week, and then subjected to 4 weeks treadmill exercise training. After training, the hearts were collected for histological observation. The level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in heart was assessed by ultraviolet spectrophotometry. The activity of lactate dehydrogenase (LDH) was determined by enzyme linked immunosorbent assay. The expression of sirtuin1 (SIRT1) mRNA was examined by real-time quantitative polymerase chain reaction (RT-qPCR). The protein expressions of SIRT1, NADPH oxidase 4 (Nox4), tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) were detected by Western blotting. The levels of reactive oxygen species (ROS) were detected by dihydroethidium (DHE) staining. Results: Compared with the C group, the expression level of cardiac Nox4 protein was increased (P<0.01), the level of MDA, activity of LDH and the level of ROS were increased significantly (P<0.01), and the expressions of TNF-α and IL-1ß protein were augmented in the heart of rats with MI (P<0.01). However, the expressions of SIRT1 mRNA and protein and the activity of SOD were obviously decreased in MI group (P<0.01). Furthermore, compared with the MI group, AIT increased the expressions of SIRT1 mRNA and protein and the activity of SOD in the heart of ME group (P<0.01); Meanwhile, the expressions of cardiac Nox4, MDA level, LDH activity and ROS level were diminished in ME group (P<0.01) as well as the decreased expressions of TNF-α and IL-1ß protein (P<0.01). SIRT1 expression was negatively related to the expressions of NOX4 and ROS. Conclusion: AIT obviously inhibited myocardial oxidative stress and inflammatory reaction, improved cardiac function in rats with MI, and the mechanism was closely related to the activation of SIRT1-Nox4-ROS signaling pathway.


Assuntos
Infarto do Miocárdio , Miocárdio , Animais , Inflamação , Masculino , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
4.
Zhongguo Zhong Yao Za Zhi ; 46(13): 3257-3269, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34396745

RESUMO

Cardiovascular diseases seriously endanger human health and life. The accompanying myocardial injury has been a focus of attention in society. Chinese medicine,serving as a natural and precious reservoir for the research and development of new drugs,is advantageous in resisting myocardial injury due to its multi-component,multi-pathway,and multi-target characteristics. In recent years,with the extensive application of culture method for isolated cardiomyocytes,a cost-effective,controllable in vitro model of cardiomyocyte injury with uniform samples is becoming a key tool for mechanism research on cardiomyocyte injury and drug development.A good in vitro model can reduce experimental and manpower cost,and also accurately stimulate clinical changes to reveal the mechanism. Therefore,the selection and establishment of in vitro model are crucial for the in-depth research. This study summarized the modeling principles,evaluation indicators,and application of more than ten models reflecting different clinical conditions,such as injuries induced by hypoxia-reoxygenation,hypertrophy,oxidative stress,inflammation,internal environmental disturbance,and toxicity. Furthermore,we analyzed advantages and technical difficulties,aiming to provide a reference for in-depth research on myocardial injury mechanism and drug development.


Assuntos
Apoptose , Miócitos Cardíacos , Hipóxia Celular , Humanos , Miocárdio , Estresse Oxidativo
5.
BMC Res Notes ; 14(1): 318, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412694

RESUMO

OBJECTIVE: Patients with thalassemia major (TM) have the highest mortality rate due to heart failure induced by myocardial iron overload. However, T2* weighted MR imaging is currently a gold standard approach for measuring iron overload. Examining ventricular volumes with magnetic resonance imaging (MR imaging) and measuring myocardial iron overload in TM patients allows for an early prediction of heart failure. This dataset includes cardiac MR images of TM patients and the control group with clinical and echocardiographic data. This dataset may be useful to researchers investigating myocardial iron overload. This dataset can also be used for medical image processing applications, such as ventricle segmentation. DATA DESCRIPTION: This study provides open-source cardiac MR images of 50 subjects and clinical and echocardiographic data. From February 2016 to January 2019, all images and clinical data were obtained from the MRI department of a general hospital in Mashhad, Iran. All the images are 16-bit gray-scale and stored in DICOM format. All patient-specific information is removed from image headers to preserve patient privacy. In addition, all images associated with each subject are compressed and saved in the RAR format.


Assuntos
Sobrecarga de Ferro , Talassemia beta , Ecocardiografia , Humanos , Sobrecarga de Ferro/diagnóstico por imagem , Imageamento por Ressonância Magnética , Miocárdio , Talassemia beta/complicações , Talassemia beta/diagnóstico por imagem
6.
Medicine (Baltimore) ; 100(33): e26995, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414983

RESUMO

ABSTRACT: Parkinson disease (PD) is a heterogeneous neurodegenerative disorder. Dopamine transporter imaging using 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (FP-CIT) and noradrenergic cardiac imaging using 123I-meta-iodobenzylguanidine (MIBG) have been used in combination or separately to study PD patients. Published results regarding uptake of the 2 tracers in each motor subtype are fairly abundant and mostly in agreement. However, data on the intrasubject association between dopaminergic and noradrenergic systems in PD patients are relatively scant and vary. We aimed to assess the intrasubject relationship between striatal dopamine transporter density using a PET tracer and cardiac sympathetic innervation in tremor-dominant subtype (TD) and akinetic-rigid subtype (AR) of PD.This study has a cross-sectional design. Thirty-one patients with early PD (17 TD/14 AR) who underwent both 123I-MIBG cardiac scintigraphy and 18F-FP-CIT PET/CT were retrospectively selected. We assessed the relationship between heart-to-mediastinum ratio (H/M) of 123I-MIBG and specific (striatal)-to-nonspecific (cerebellar) dopamine transporter binding ratio (S/N) measured from 4 separate regions-of-interest (bilateral caudate nuclei and lentiform nuclei) of 18F-FP-CIT in each motor subtype.S/N of all 4 striatal regions were significantly lower in the AR subgroup than in the TD subgroup. H/M was not significantly different. There was a significant intrasubject correlation between H/M and S/N of the lentiform nucleus in AR-PD but no correlation between H/M and any of 4 S/N in TD-PD.Our data suggest a coupled degeneration of nigrostriatal dopaminergic and myocardial sympathetic denervation in AR subtype, but not in TD subtype, of early PD patients. These different results between the 2 motor subtypes likely reflects the heterogeneous pathophysiology of PD.


Assuntos
3-Iodobenzilguanidina/metabolismo , Radioisótopos do Iodo/metabolismo , Miocárdio/metabolismo , Doença de Parkinson/metabolismo , 3-Iodobenzilguanidina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Radioisótopos do Iodo/análise , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio/métodos , Tomografia por Emissão de Pósitrons/métodos
7.
Nat Commun ; 12(1): 4963, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400625

RESUMO

We have shown that calcium-activated potassium (KCa)-channels regulate fundamental progenitor-cell functions, including proliferation, but their contribution to cell-therapy effectiveness is unknown. Here, we test the participation of KCa-channels in human heart explant-derived cell (EDC) physiology and therapeutic potential. TRAM34-sensitive KCa3.1-channels, encoded by the KCNN4 gene, are exclusively expressed in therapeutically bioactive EDC subfractions and maintain a strongly polarized resting potential; whereas therapeutically inert EDCs lack KCa3.1 channels and exhibit depolarized resting potentials. Somatic gene transfer of KCNN4 results in membrane hyperpolarization and increases intracellular [Ca2+], which boosts cell-proliferation and the production of pro-healing cytokines/nanoparticles. Intramyocardial injection of EDCs after KCNN4-gene overexpression markedly increases the salutary effects of EDCs on cardiac function, viable myocardium and peri-infarct neovascularization in a well-established murine model of ischemic cardiomyopathy. Thus, electrophysiological engineering provides a potentially valuable strategy to improve the therapeutic value of progenitor cells for cardioprotection and possibly other indications.


Assuntos
Cálcio/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Fenômenos Eletrofisiológicos , Coração , Canais de Potássio Cálcio-Ativados/metabolismo , Potássio/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Isquemia , Potenciais da Membrana/fisiologia , Camundongos , Miocárdio/metabolismo , Nanopartículas , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Cálcio-Ativados/genética , Células-Tronco
8.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361060

RESUMO

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.


Assuntos
Sistema Nervoso Central/patologia , Fibrose/patologia , Miocárdio/patologia , Neurônios/patologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Sistema Nervoso Central/metabolismo , Feminino , Fibrose/metabolismo , Proteínas HMGA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Neurônios/metabolismo , Fenótipo , Fosforilação
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(7): 689-696, 2021 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34382584

RESUMO

OBJECTIVES: Tumor necrosis factor α stimulated gene 6 (TSG-6) protein is an inflammation-inducing protein. In recent years, TSG-6 protein has been found to play an anti-inflammatory and anti-fibrosis role in a variety of disease models. The level of TSG-6 protein in circulating blood is considered to be a biological indicator for the evaluation of acute coronary syndrome, severe infection, and other diseases, and it is closely related to the prognosis. The clinical correlation between TSG-6 protein and dilated cardiomyopathy (DCM) patients with heart failure has not been reported. This study aims to investigate the changes of plasma TSG-6 protein levels in cardiomyopathy patients with heart failure and its correlation with cardiac function, myocardial fibrosis, and prognosis. METHODS: Based on the prospective studies, a number of 90 DCM patients with heart failure were selected as a DCM heart failure group from Dec.1, 2019 to Sept.1, 2020. Thirty-nine healthy people were served as a control group. Plasma TSG-6, Collagen Ⅰ, Collagen III, and α-smooth muscle actin (α-SMA) were measured with ELISA test. Echocardiography was used to evaluate the structure and function of the heart. DCM patients with heart failure were followed up for 3 months. The patients were assigned into 2 groups according to whether they had major adverse cardiovascular events (MACE). The general clinical data, plasma TSG-6, Collagen Ⅰ, Collagen III, and α-SMA protein levels were compared between the control group and the DCM heart failure group. At the same time, the correlation between plasma TSG-6 protein level and cardiac function grade, myocardial fibrosis or prognosis of patients in the DCM heart failure group was analyzed. RESULTS: Compared with the control group, the heart rate, TSG-6, Collagen Ⅰ, Collage III, α-SMA, hemoglobin, atrial natriuretic peptide (NT-proBNP), hypersensitive C-reactive protein, aspartate aminotransferase, serum creatinine, lactate dehydrogenase, and left ventricular end diastolic diameter (LVEDD) increased significantly (all P<0.001). High-density lipoprotein, left ventricular short axis shortening rate (LVFS), and left ventricular ejection fraction (LVEF) decreased significantly in the DCM heart failure group (all P<0.001). Plasma levels of TSG-6 were positively correlated with NT-proBNP, Collagen Ⅰ, Collagen III, α-SMA, and LVEDD (all P<0.001), while they were negatively correlated with LVFS and LVEF (all P<0.001). With the increase of NYHA heart function classification, plasma levels of TSG-6, Collagen Ⅰ, Collagen III, and α-SMA increased significantly (all P<0.001). The increases in plasma levels of NT-proBNP and TSG-6 was associated with poor prognosis in DCM patients with heart failure (all P<0.05). The sensitivity and specificity of plasma NT-proBNP for evaluating the prognosis of DCM heart failure were 76.2% and 68.1%, respectively. The sensitivity and specificity of plasma TSG-6 for evaluating the prognosis of DCM heart failure were 95.2% and 66.7%, respectively. The sensitivity and specificity of plasma TSG-6 combined with NT-proBNP for prognostic evaluation of DCM heart failure were 85.7% and 81.2%, respectively. The specificity of plasma TSG-6 combined with NT-proBNP for the prognosis of heart failure was better than that of NT-proBNP or TSG-6 alone (P<0.001). CONCLUSIONS: The plasma levels TSG-6 in DCM patients with heart failure increase significantly, and the plasma levels TSG-6 could be used as a new predictor for cardiac function, myocardial fibrosis, and prognosis.


Assuntos
Cardiomiopatia Dilatada , Moléculas de Adesão Celular/sangue , Insuficiência Cardíaca , Miocárdio/patologia , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Fibrose , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Prognóstico , Estudos Prospectivos , Volume Sistólico , Função Ventricular Esquerda
11.
Eur Rev Med Pharmacol Sci ; 25(15): 5063-5069, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34355379

RESUMO

OBJECTIVE: Vaccine-induced immune thrombocytopenia (VITT) is a new syndrome occurring primarily in healthy young adults, with a female predominance, after receiving the first dose of ChAdOx1 nCoV-19 vaccine. We describe VITT syndrome characterized by severe thrombosis and thrombocytopenia found in our patient, with fatal outcome. CASE REPORT: A 58-year-old man, after 13 days from the first administration of ChAdOx1 nCoV-19 vaccine (AstraZeneca), presented with abdominal pain, diarrhea and vomitus. Laboratory tests revealed a severe thrombocytopenia, low fibrinogen serum levels and marked increase of D-dimer serum levels. The patient quickly developed a multiple organ failure, till death, three days after the hospital admission. RESULTS: At histology, in the lungs, interalveolar septa appeared thickened with microthrombi in the capillaries and veins. Interalveolar septa appeared thickened and showed vascular proliferation. Thrombi were detected in the capillaries of glomerular tufts. In the hearth, thrombi were observed in veins and capillaries. In the liver, voluminous fibrin thrombi were diffusely observed in the branches of the portal vein. Microthrombi were also found in the vasa vasorum of the wall of abdominal aorta. In the brain, microthrombi were observed in the capillaries of the choroid plexuses. Diffuse hemorrhagic necrosis was observed in the intestinal wall with marked congestion of the venous vessels. CONCLUSIONS: In our patient, the majority of data necessary for a VITT final diagnosis were present: thrombocytopenia and thrombosis in pulmonary, portal, hepatic, renal and mesenteric veins, associated with a marked increase of D-dimer serum levels. The finding of cerebral thrombosis in choroid plexuses, is a new finding in VITT. These features are suggestive for a very aggressive form of VITT.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Púrpura Trombocitopênica Idiopática/etiologia , Trombose/etiologia , Aorta/patologia , COVID-19/sangue , Vacinas contra COVID-19/administração & dosagem , Plexo Corióideo/patologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Íleo/patologia , Rim/patologia , Fígado/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Púrpura Trombocitopênica Idiopática/sangue , Trombose/sangue
12.
FASEB J ; 35(9): e21799, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339055

RESUMO

Cardiac fibroblasts (CFBs) support heart function by secreting extracellular matrix (ECM) and paracrine factors, respond to stress associated with injury and disease, and therefore are an increasingly important therapeutic target. We describe how developmental lineage of human pluripotent stem cell-derived CFBs, epicardial (EpiC-FB), and second heart field (SHF-FB) impacts transcriptional and functional properties. Both EpiC-FBs and SHF-FBs exhibited CFB transcriptional programs and improved calcium handling in human pluripotent stem cell-derived cardiac tissues. We identified differences including in composition of ECM synthesized, secretion of growth and differentiation factors, and myofibroblast activation potential, with EpiC-FBs exhibiting higher stress-induced activation potential akin to myofibroblasts and SHF-FBs demonstrating higher calcification and mineralization potential. These phenotypic differences suggest that EpiC-FBs have utility in modeling fibrotic diseases while SHF-FBs are a promising source of cells for regenerative therapies. This work directly contrasts regional and developmental specificity of CFBs and informs CFB in vitro model selection.


Assuntos
Linhagem da Célula/fisiologia , Miofibroblastos/fisiologia , Células-Tronco Pluripotentes/fisiologia , Diferenciação Celular/fisiologia , Células Cultivadas , Matriz Extracelular/fisiologia , Humanos , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Fenótipo , Transcrição Genética/fisiologia
13.
Nat Biomed Eng ; 5(8): 880-896, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34426676

RESUMO

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.


Assuntos
Células Endoteliais/transplante , Coração/fisiologia , Infarto do Miocárdio/terapia , Miócitos de Músculo Liso/transplante , Regeneração , Animais , Ácido Ascórbico/farmacologia , Proteína Morfogenética Óssea 4/farmacologia , Reprogramação Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Junções Comunicantes/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Neovascularização Fisiológica , Transcriptoma
14.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445494

RESUMO

Despite significant advances in treatment of acute coronary syndromes (ACS) many subjects still develop heart failure due to significantly reduced ejection fraction. Currently, there are no commonly available treatment strategies that replace the infarcted/dysfunctional myocardium. Therefore, understanding the mechanisms that control the regeneration of the heart muscle is important. The development of new coronary vessels plays a pivotal role in cardiac regeneration. Employing microarray expression assays and RT-qPCR validation expression pattern of genes in long-term primary cultured cells isolated form the right atrial appendage (RAA) and right atrium (RA) was evaluated. After using DAVID software, it indicated the analysis expression profiles of genes involved in ontological groups such as: "angiogenesis", "blood vessel morphogenesis", "circulatory system development", "regulation of vasculature development", and "vasculature development" associated with the process of creation new blood vessels. The performed transcriptomic comparative analysis between two different compartments of the heart muscle allowed us to indicate the presence of differences in the expression of key transcripts depending on the cell source. Increases in culture intervals significantly increased expression of SFRP2, PRRX1 genes and some other genes involved in inflammatory process, such as: CCL2, IL6, and ROBO1. Moreover, the right atrial appendage gene encoding lysyl oxidase (LOX) showed much higher expression compared to the pre-cultivation state.


Assuntos
Vasos Coronários/crescimento & desenvolvimento , Perfilação da Expressão Gênica/métodos , Desenvolvimento Muscular , Miocárdio/citologia , Animais , Células Cultivadas , Vasos Coronários/química , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Miocárdio/química , Análise de Sequência com Séries de Oligonucleotídeos , Cultura Primária de Células , Suínos , Sequenciamento Completo do Exoma
15.
Life Sci ; 283: 119849, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343539

RESUMO

AIMS: Cardiotoxicity of doxorubicin frequently complicates treatment outcome. Aberrantly activated calcium/calmodulin pathway can eventually trigger signaling cascades that mediate cardiotoxicity. Therefore, we tested the hypothesis that trifluoperazine, a strong calmodulin antagonist, may alleviate this morbidity. MATERIALS AND METHODS: Heart failure and cardiotoxicity were assessed via echocardiography, PCR, immunohistochemistry, histopathology, Masson's trichrome staining and transmission electron microscopy. Whereas liver and kidney structural and functional alterations were evaluated histopathologically and biochemically. KEY FINDINGS: Results revealed that combination treatment with trifluoperazine could overcome doxorubicin-induced heart failure with reduced ejection fraction. Moreover, heart weight/body weight ratio and histopathological examination showed that trifluoperazine mitigated doxorubicin-induced cardiac atrophy, inflammation and myofibril degeneration. Transmission electron microscopy further confirmed the marked restoration of the left ventricular ultrastructures by trifluoperazine pretreatment. In addition, Masson's trichrome staining revealed that trifluoperazine could significantly inhibit doxorubicin-induced left ventricular remodeling by fibrosis. Of note, doxorubicin induced the expression of myocardial nuclear NF-κB-p65 and caspase-3 which were markedly inhibited by trifluoperazine, suggesting that cardioprotection conferred by trifluoperazine involved, at least in part, suppression of NF-κB and apoptosis. Furthermore, biochemical and histopathological examinations showed that trifluoperazine improved doxorubicin-induced renal and hepatic impairments both functionally and structurally. SIGNIFICANCE: In conclusion, the present in vivo study is the first to provide evidences underscoring the protective effects of trifluoperazine that may pave the way for repurposing this calmodulin antagonist in ameliorating organ toxicity by doxorubicin.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade , Cardiotoxinas/efeitos adversos , Doxorrubicina/efeitos adversos , Miocárdio/metabolismo , Fator de Transcrição RelA/metabolismo , Trifluoperazina/farmacologia , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxinas/farmacologia , Caspase 3/metabolismo , Doxorrubicina/farmacologia , Masculino , Camundongos , Miocárdio/patologia
16.
Life Sci ; 283: 119866, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352257

RESUMO

AIMS: Morphine, a commonly used drug for anesthesia, affects lipid metabolism in different tissues, but the mechanism is currently unclear. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme responsible for the first step of triglyceride (TG) hydrolysis. Here we aim to investigate whether ATGL phosphorylation is involved in morphine-induced TG accumulation. MAIN METHODS: Oil red O staining and TG content analysis were used to detect the effect of morphine on lipid storage. A series of ATGL phosphoamino acid site mutant plasmids were constructed by gene synthesis and transfected to HL-1 cells to evaluate the phosphorylation levels of ATGL phosphoamino acid in morphine-treated HL-1 cells with immunoprecipitation and immunoblotting assay. KEY FINDINGS: Morphine acute treatment induced excessive accumulation of TG and decreased the phosphorylation level of ATGL Ser406 in HL-1 cells. Of note, the phosphorylation positive mutation of ATGL Ser406 to aspartic acid effectively reversed morphine-induced excessive accumulation of TG in HL-1 cells. SIGNIFICANCE: This discovery will help to fully understand the lipid regulation function of morphine in a new scope. In addition, it will expand the phosphorylation research of ATGL more comprehensively and provide powerful clues for lipid metabolism regulation.


Assuntos
Lipase/metabolismo , Morfina/farmacologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Triglicerídeos/biossíntese , Animais , Linhagem Celular , Masculino , Camundongos , Morfina/farmacocinética , Miocárdio/patologia , Miócitos Cardíacos/patologia , Fosforilação/efeitos dos fármacos
17.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360813

RESUMO

Proper cardiac function depends on the coordinated expression of multiple gene networks related to fuel utilization and mitochondrial ATP production, heart contraction, and ion transport. Key transcriptional regulators that regulate these gene networks have been identified. Among them, estrogen-related receptors (ERRs) have emerged as crucial modulators of cardiac function by regulating cellular metabolism and contraction machinery. Consistent with this role, lack of ERRα or ERRγ results in cardiac derangements that lead to functional maladaptation in response to increased workload. Interestingly, metabolic inflexibility associated with diabetic cardiomyopathy has been recently associated with increased mitochondrial fatty acid oxidation and expression of ERRγ, suggesting that sustained expression of this nuclear receptor could result in a cardiac pathogenic outcome. Here, we describe the generation of mice with cardiac-specific overexpression of ERRγ, which die at young ages due to heart failure. ERRγ transgenic mice show signs of dilated cardiomyopathy associated with cardiomyocyte hypertrophy, increased cell death, and fibrosis. Our results suggest that ERRγ could play a role in mediating cardiac pathogenic responses.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptores de Estrogênio/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/patologia , Miócitos Cardíacos/patologia
18.
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