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1.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805800

RESUMO

Cyclin-dependent kinases (CDKs) are involved in many crucial processes, such as cell cycle and transcription, as well as communication, metabolism, and apoptosis. The kinases are organized in a pathway to ensure that, during cell division, each cell accurately replicates its DNA, and ensure its segregation equally between the two daughter cells. Deregulation of any of the stages of the cell cycle or transcription leads to apoptosis but, if uncorrected, can result in a series of diseases, such as cancer, neurodegenerative diseases (Alzheimer's or Parkinson's disease), and stroke. This review presents the current state of knowledge about the characteristics of cyclin-dependent kinases as potential pharmacological targets.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ciclo Celular/genética , Quinases Ciclina-Dependentes/genética , Neoplasias/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Cardiomegalia/tratamento farmacológico , Cardiomegalia/enzimologia , Cardiomegalia/genética , Cardiomegalia/patologia , Fármacos Cardiovasculares/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Regulação da Expressão Gênica , Humanos , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
2.
Nat Commun ; 12(1): 1547, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707436

RESUMO

Hypertension, exercise, and pregnancy are common triggers of cardiac remodeling, which occurs primarily through the hypertrophy of individual cardiomyocytes. During hypertrophy, stress-induced signal transduction increases cardiomyocyte transcription and translation, which promotes the addition of new contractile units through poorly understood mechanisms. The cardiomyocyte microtubule network is also implicated in hypertrophy, but via an unknown role. Here, we show that microtubules are indispensable for cardiac growth via spatiotemporal control of the translational machinery. We find that the microtubule motor Kinesin-1 distributes mRNAs and ribosomes along microtubule tracks to discrete domains within the cardiomyocyte. Upon hypertrophic stimulation, microtubules redistribute mRNAs and new protein synthesis to sites of growth at the cell periphery. If the microtubule network is disrupted, mRNAs and ribosomes collapse around the nucleus, which results in mislocalized protein synthesis, the rapid degradation of new proteins, and a failure of growth, despite normally increased translation rates. Together, these data indicate that mRNAs and ribosomes are actively transported to specific sites to facilitate local translation and assembly of contractile units, and suggest that properly localized translation - and not simply translation rate - is a critical determinant of cardiac hypertrophy. In this work, we find that microtubule based-transport is essential to couple augmented transcription and translation to productive cardiomyocyte growth during cardiac stress.


Assuntos
Cardiomegalia/patologia , Microtúbulos/metabolismo , Miócitos Cardíacos/patologia , Biossíntese de Proteínas/fisiologia , RNA Mensageiro/metabolismo , Ribossomos/metabolismo , Animais , Remodelamento Atrial/fisiologia , Transporte Biológico/fisiologia , Células Cultivadas , Humanos , Cinesina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Transdução de Sinais/fisiologia , Remodelação Ventricular/fisiologia
3.
Am J Physiol Heart Circ Physiol ; 320(4): H1470-H1485, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577435

RESUMO

The insulin-like growth factor 1 receptor (IGF1R) and phosphoinositide 3-kinase p110α (PI3K) are critical regulators of exercise-induced physiological cardiac hypertrophy and provide protection in experimental models of pathological remodeling and heart failure. Forkhead box class O1 (FoxO1) is a transcription factor that regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K activation in vitro, but its role in physiological hypertrophy in vivo was unknown. We generated cardiomyocyte-specific FoxO1 knockout (cKO) mice and assessed the phenotype under basal conditions and settings of physiological hypertrophy induced by 1) swim training or 2) cardiac-specific transgenic expression of constitutively active PI3K (caPI3KTg+). Under basal conditions, male and female cKO mice displayed mild interstitial fibrosis compared with control (CON) littermates, but no other signs of cardiac pathology were present. In response to exercise training, female CON mice displayed an increase (∼21%) in heart weight normalized to tibia length vs. untrained mice. Exercise-induced hypertrophy was blunted in cKO mice. Exercise increased cardiac Akt phosphorylation and IGF1R expression but was comparable between genotypes. However, differences in Foxo3a, Hsp70, and autophagy markers were identified in hearts of exercised cKO mice. Deletion of FoxO1 did not reduce cardiac hypertrophy in male or female caPI3KTg+ mice. Cardiac Akt and FoxO1 protein expressions were significantly reduced in hearts of caPI3KTg+ mice, which may represent a negative feedback mechanism from chronic caPI3K, and negate any further effect of reducing FoxO1 in the cKO. In summary, FoxO1 contributes to exercise-induced hypertrophy. This has important implications when one is considering FoxO1 as a target for treating the diseased heart.NEW & NOTEWORTHY Regulators of exercise-induced physiological cardiac hypertrophy and protection are considered promising targets for the treatment of heart failure. Unlike pathological hypertrophy, the transcriptional regulation of physiological hypertrophy has remained largely elusive. To our knowledge, this is the first study to show that the transcription factor FoxO1 is a critical mediator of exercise-induced cardiac hypertrophy. Given that exercise-induced hypertrophy is protective, this finding has important implications when one is considering FoxO1 as a target for treating the diseased heart.


Assuntos
Cardiomegalia Induzida por Exercícios , Cardiomegalia/enzimologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Proteína Forkhead Box O1/metabolismo , Miócitos Cardíacos/enzimologia , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Ativação Enzimática , Feminino , Fibrose , Proteína Forkhead Box O1/deficiência , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP70/metabolismo , Masculino , Camundongos Knockout , Miócitos Cardíacos/patologia , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Natação
4.
Am J Forensic Med Pathol ; 42(1): 1-8, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416234

RESUMO

ABSTRACT: The 2019 novel coronavirus disease (COVID-19) has spread worldwide, infiltrating, infecting, and devastating communities in all locations of varying demographics. An overwhelming majority of published literature on the pathologic findings associated with COVID-19 is either from living clinical cohorts or from autopsy findings of those who died in a medical care setting, which can confound pure disease pathology. A relatively low initial infection rate paired with a high biosafety level enabled the New Mexico Office of the Medical Investigator to conduct full autopsy examinations on suspected COVID-19-related deaths. Full autopsy examination on the first 20 severe acute respiratory syndrome coronavirus 2-positive decedents revealed that some extent of diffuse alveolar damage in every death due to COVID-19 played some role. The average decedent was middle-aged, male, American Indian, and overweight with comorbidities that included diabetes, ethanolism, and atherosclerotic and/or hypertensive cardiovascular disease. Macroscopic thrombotic events were seen in 35% of cases consisting of pulmonary thromboemboli and coronary artery thrombi. In 2 cases, severe bacterial coinfections were seen in the lungs. Those determined to die with but not of severe acute respiratory syndrome coronavirus 2 infection had unremarkable lung findings.


Assuntos
/mortalidade , Pulmão/patologia , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Autopsia , Índice de Massa Corporal , Edema Encefálico/patologia , Cardiomegalia/patologia , Comorbidade , Trombose Coronária/patologia , Bases de Dados Factuais , Fígado Gorduroso/patologia , Feminino , Patologia Legal , Glomerulosclerose Segmentar e Focal/patologia , Hepatomegalia/patologia , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Nefroesclerose/patologia , New Mexico/epidemiologia , Sobrepeso/epidemiologia , Pandemias , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/patologia , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/patologia , Distribuição por Sexo , Streptococcus pneumoniae/isolamento & purificação , Tomografia Computadorizada por Raios X , Corpo Vítreo/química , Imagem Corporal Total
5.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495819

RESUMO

High­mobility group box 1 (HMGB1) is released by necrotic cells and serves an important role in cardiovascular pathology. However, the effects of HMGB1 in cardiomyocyte hypertrophy remain unclear. Therefore, the aim of the present study was to investigate the potential role of HMGB1 in cardiomyocyte hypertrophy and the underlying mechanisms of its action. Neonatal mouse cardiomyocytes (NMCs) were co­cultured with recombinant HMGB1 (rHMGB1). Wortmannin was used to inhibit PI3K activity in cardiomyocytes. Subsequently, atrial natriuretic peptide (ANP), 14­3­3 and phosphorylated­Akt (p­Akt) protein levels were detected using western blot analysis. In addition, nuclear factor of activated T cells 3 (NFAT3) protein levels were measured by western blot analysis and observed in NMCs under a confocal microscope. The results revealed that rHMGB1 increased ANP and p­Akt, and decreased 14­3­3η protein levels. Furthermore, wortmannin abrogated the effects of rHMGB1 on ANP, 14­3­3η and p­Akt protein levels. In addition, rHMGB1 induced nuclear translocation of NFAT3, which was also inhibited by wortmannin pretreatment. The results of this study suggest that rHMGB1 induces cardiac hypertrophy by regulating the 14­3­3η/PI3K/Akt/NFAT3 signaling pathway.


Assuntos
Proteínas 14-3-3/metabolismo , Cardiomegalia/metabolismo , Proteína HMGB1/efeitos adversos , Miócitos Cardíacos/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Feminino , Proteína HMGB1/farmacologia , Camundongos , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/genética , Proteínas Recombinantes
6.
J Ethnopharmacol ; 264: 113346, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32896627

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The prevalence of cardiovascular diseases (CVDs) has been increasing worldwide. Despite significant improvements in therapeutics and on-going developments of novel targeted-treatment regimens, cardiac diseases lack effective preventive and curative therapies with minimal side effects. Therefore, there is an urgent need to identify and propagate alternative and complementary therapies against cardiovascular diseases. Some traditional Chinese medicines can contribute to the prevention and treatment of CVDs and other chronic diseases, with few side effects. Hirudo, a medicinal leech, has been acclaimed for improving blood circulation and overcoming blood stagnation; however, the precise molecular mechanisms of leech extract treatment against pathological cardiac remodeling remain elusive. In this study, we aimed to delineate the molecular mechanisms of medicinal leech extract in the treatment of cardiac hypertrophy and fibrosis, using both in vitro and in vivo assessments. MATERIALS AND METHODS: We conducted in vitro and in vivo animal experiments, including cell-viability assays, fluorescence microscopy, immunoblotting, immunohistochemistry, and Masson's trichrome staining. RESULTS: Pre-treatment with leech extract conferred a survival benefit to spontaneously-hypertensive rats (SHRs) and significantly reduced angiotensin II (ANG II)-induced cardiac hypertrophy and fibrosis. ANG II-stimulated cardiac hypertrophy markers were attenuated by leech extract treatment, versus controls. Translational expression of stress-associated mitogen-activated protein kinases (MAPKs) was also repressed. In vivo, leech extract treatment significantly ameliorated the cardiac hypertrophy phenotype in SHRs and diminished interstitial fibrosis, accompanied with reduced fibrosis markers. CONCLUSION: Leech extract treatment under a hypertensive condition exerted significant cardio-protective benefits by reducing the expression of cardiac hypertrophy-related transcription factors, stress-associated MAPKs, and fibrosis mediators. Our findings imply that medicinal leach extract may be effective against hypertension-induced cardiac hypertrophy and fibrosis.


Assuntos
Cardiomegalia/tratamento farmacológico , Cardiotônicos/uso terapêutico , Hirudo medicinalis , Hipertensão/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Animais , Fatores Biológicos , Cardiomegalia/etiologia , Cardiomegalia/patologia , Cardiotônicos/isolamento & purificação , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Fibrose , Hipertensão/complicações , Hipertensão/patologia , Sanguessugas , Masculino , Miócitos Cardíacos/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
7.
Am J Forensic Med Pathol ; 41(4): e61-e63, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32969849

RESUMO

The autopsy findings for 3 cases of SARS-(CoV-2) pneumonia-related deaths are reported with pulmonary histology and immunohistochemistry findings. In 2 cases (cases 1 and 2), the time interval from presentation to death was approximately 1 week, whereas for case 3, the time interval from presentation to death was hours. Case 1 and case 2 presented with shortness of breath, cough, and flu-like symptoms. The decedent from case 3 died shortly after presenting to a local emergency room with high fever, chest and abdominal pain, and shortness of breath. All 3 cases had 1 or more comorbidities. The postmortem interval for cases 1 and 2 was 2 weeks as they died at sea and were stored on board within the respective cruise ships' refrigeration units, whereas case 3 was examined within 24 hours of death. The autopsies were conducted at the Miami-Dade County Medical Examiners Department under routine infectious precautions. Salient clinical history and autopsy findings are summarized. Microscopic examination revealed pneumonia with associated atypical endovascular cells.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Adulto , Autopsia , Cardiomegalia/complicações , Cardiomegalia/patologia , Círculo Arterial do Cérebro/patologia , Comorbidade , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/patologia , Infecções por Coronavirus/complicações , Complicações do Diabetes/patologia , Evolução Fatal , Feminino , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Obesidade/complicações , Obesidade/patologia , Pandemias , Pneumonia Viral/complicações , Edema Pulmonar/complicações , Edema Pulmonar/patologia , Uso de Tabaco/patologia
8.
Life Sci ; 260: 118378, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32898528

RESUMO

AIMS: Pathological cardiac hypertrophy (CH) is one of the main risk factors for heart failure and cardiac death. Mitochondrial dysfunction and oxidative stress often occur in hypertrophic cardiomyocytes. It was recently proposed that deficiency or decreased activity of glucose-6-phosphate dehydrogenase (G6PD) may be related to the development of CH. This study aimed to investigate the expression of G6PD in CH and its regulatory role in mitochondrial dysfunction and oxidative stress of CH cells. MAIN METHODS: Phenylephrine (PE) was used to create an in vitro model of CH. Using RT-qPCR and western blotting, the expression levels of target mRNAs and proteins were measured. ELISA assays and commercial kits based on spectrophotometry or colorimetry were used to measure mitochondrial function and oxidative stress. TargetScan and luciferase reporter gene assays were utilized for combination prediction and validation. CCK-8 and TUNEL kit were used to determine cell viability and apoptosis. KEY FINDINGS: The results showed that G6PD overexpression attenuated the decreases of mitochondrial respiration, ATP, ATP synthetase and mitochondrial membrane potential induced by PE, as well as the increases of LDH release and apoptosis. Besides, PE elevated ROS activity, NO and MDA contents, and reduced SOD, CAT levels and cell viability. These effects were hindered by G6PD overexpression. MiR-24 was found to directly bind to G6PD at the motif of CUGAGCC and regulated its expression, furtherly, influenced the G6PD-mediated mitochondrial dysfunction and oxidative stress of CH cells. SIGNIFICANCE: Generally, our study demonstrated that miR-24/G6PD regulates mitochondrial dysfunction and oxidative stress in CH cells, representing a new sight for CH therapy.


Assuntos
Cardiomegalia/patologia , Glucosefosfato Desidrogenase/metabolismo , MicroRNAs/genética , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/efeitos adversos , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiotônicos/efeitos adversos , Glucosefosfato Desidrogenase/genética , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
9.
Phytomedicine ; 79: 153322, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920286

RESUMO

BACKGROUND: Gut-heart axis has emerged as a novel concept to provide new insights into the complex mechanisms of heart failure (HF) and offer new therapeutic targets. Cardiac hypertrophy (CH) is one of the etiological agents contributing to the development of HF. Baoyuan Decoction (BYD), a traditional Chinese medicine (TCM) formula, exhibits unambiguous effects on treating CH and preventing HF. Previously, we have reported that BYD-targeted endogenous metabolites are potentially linked to gut microbiota metabolism, but the contribution of gut microbiota and metabolic interaction to the cardioprotective efficacy of BYD remains to be elucidated. PURPOSE: To investigate whether the gut microbiota plays a key role in anti-CH effects of BYD. STUDY DESIGN: A comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and microflora suppression model was adopted to investigate the links between the microbiota-host metabolic interaction and BYD efficacy in CH rats. METHOD: Firstly, the efficacy evaluation of BYD in treating chronic isoproterenol (ISO)-induced CH rats was performed by using multiple pharmacodynamic approaches. Then, the fecal metabolomics and 16S rRNA sequencing techniques were used to obtain the microbial and metabolic features of BYD against CH. After that, the potential gut-heart axis-based mechanism of BYD against CH was predicted by bioinformatic network analysis and validated by multiple molecular biology approaches. Finally, the antibiotics (AB)-induced gut microbiota suppression was employed to investigate whether the anti-CH effects of BYD is associated with the gut microflora. RESULTS: The fecal microbial communities and metabolic compositions were significantly altered in ISO-induced CH rats, while BYD effectively ameliorated the CH-associated gut microbiota dysbiosis, especially of Firmicutes and Bacteroidetes, and time-dependently alleviated the disturbance of fecal metabolome and reversed the changes of key CH and gut microbiota-related metabolites, such as short/medium chain fatty acids, primary/secondary bile acids, and amino acids. The mechanism study showed that the anti-CH effect of BYD was related to inhibition of the derivatives of arginine and tryptophan and their downstream pro-hypertrophic, pro-inflammatory, and pro-oxidant signaling pathways. The following microflora suppression test showed that BYD-mediated myocardial protection was decreased either in pharmacodynamics or in metabolic modulation. CONCLUSION: This study demonstrates that the protection of BYD against CH is partially gut microbiota dependent, and the regulatory effects of gut metabolism-related tryptophan and arginine derivatives is an important cardioprotection mechanism of BYD.


Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/microbiologia , Cardiotônicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Cardiomegalia/patologia , Disbiose/tratamento farmacológico , Disbiose/etiologia , Disbiose/microbiologia , Fezes/química , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Coração/efeitos dos fármacos , Isoproterenol/toxicidade , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia , RNA Ribossômico 16S/análise , RNA Ribossômico 16S/genética , Ratos Sprague-Dawley
10.
Nature ; 584(7820): 279-285, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760005

RESUMO

In pathophysiology, reactive oxygen species oxidize biomolecules that contribute to disease phenotypes1. One such modification, 8-oxoguanine2 (o8G), is abundant in RNA3 but its epitranscriptional role has not been investigated for microRNAs (miRNAs). Here we specifically sequence oxidized miRNAs in a rat model of the redox-associated condition cardiac hypertrophy4. We find that position-specific o8G modifications are generated in seed regions (positions 2-8) of selective miRNAs, and function to regulate other mRNAs through o8G•A base pairing. o8G is induced predominantly at position 7 of miR-1 (7o8G-miR-1) by treatment with an adrenergic agonist. Introducing 7o8G-miR-1 or 7U-miR-1 (in which G at position 7 is substituted with U) alone is sufficient to cause cardiac hypertrophy in mice, and the mRNA targets of o8G-miR-1 function in affected phenotypes; the specific inhibition of 7o8G-miR-1 in mouse cardiomyocytes was found to attenuate cardiac hypertrophy. o8G-miR-1 is also implicated in patients with cardiomyopathy. Our findings show that the position-specific oxidation of miRNAs could serve as an epitranscriptional mechanism to coordinate pathophysiological redox-mediated gene expression.


Assuntos
Cardiomegalia/genética , Cardiomegalia/patologia , Inativação Gênica , MicroRNAs/química , MicroRNAs/metabolismo , Animais , Pareamento de Bases , Linhagem Celular , Modelos Animais de Doenças , Guanina/análogos & derivados , Guanina/análise , Guanina/química , Guanina/metabolismo , Humanos , Camundongos , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxirredução , Ratos , Transcrição Genética/genética , Transcriptoma/genética
11.
PLoS One ; 15(7): e0232507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645007

RESUMO

Sex-related differences in cardiovascular diseases are highly complex in humans and model-dependent in experimental laboratory animals. The objective of this work was to comprehensively investigate key sex differences in the response to acute and prolonged adrenergic stimulation in C57Bl/6NCrl mice. Cardiac function was assessed by trans-thoracic echocardiography before and after acute adrenergic stimulation (a single sub-cutaneous dose of isoproterenol 10 mg/kg) in 15 weeks old male and female C57Bl/6NCrl mice. Thereafter, prolonged adrenergic stimulation was achieved by sub-cutaneous injections of isoproterenol 10 mg/kg/day for 14 days in male and female mice. Cardiac function and morphometry were assessed by trans-thoracic echocardiography on the 15th day. Thereafter, the mice were euthanized, and the hearts were collected. Histopathological analysis of myocardial tissue was performed after staining with hematoxylin & eosin, Masson's trichrome and MAC-2 antibody. Gene expression of remodeling and fibrotic markers was assessed by real-time PCR. Cardiac function and morphometry were also measured before and after isoproterenol 10 mg/kg/day for 14 days in groups of gonadectomized male and female mice and sham-operated controls. In the current work, there were no statistically significant differences in the positive inotropic and chronotropic effects of isoproterenol between male and female C57Bl/6NCrl. After prolonged adrenergic stimulation, there was similar degree of cardiac dysfunction, cardiac hypertrophy, and myocardial fibrosis in male and female mice. Similarly, prolonged isoproterenol administration induced hypertrophic and fibrotic genes in hearts of male and female mice to the same extent. Intriguingly, gonadectomy of male and female mice did not have a significant impact on isoproterenol-induced cardiac dysfunction as compared to sham-operated animals. The current work demonstrated lack of significant sex-related differences in isoproterenol-induced cardiac hypertrophy, dysfunction, and fibrosis in C57Bl/6NCrl mice. This study suggests that female sex may not be sufficient to protect the heart in this model of isoproterenol-induced cardiac dysfunction and underscores the notion that sexual dimorphism in cardiovascular diseases is highly model-dependent.


Assuntos
Cardiopatias/fisiopatologia , Caracteres Sexuais , Animais , Biomarcadores/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Isoproterenol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia
12.
Arch Biochem Biophys ; 689: 108405, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32439330

RESUMO

Cardiac hypertrophy is an adaptive response to hemodynamic stress to compensate for cardiac dysfunction. MicroRNAs can regulate cardiac function and play a vital role in the regulation of cardiac hypertrophy. In the current study, in vivo and vitro hypertrophy models are established to explore the role of miR-27b and to elucidate the underlying mechanism in cardiac hypertrophy. Expression of miR-27b was down-regulated in mice with cardiac hypertrophy. The cardiac function of the mice with cardiac hypertrophy could be restored with the overexpression of miR-27b, this is observed in terms of decreasing LVEDd, LVESd, and increasing LVFS, LVEF. This study also predicted and confirmed that galectin-3 is a target gene of miR-27b. Depletion of galectin-3 significantly attenuated hypertrophy of hearts in both in vitro and in vivo tests. In conclusion, MiR-27b be used to exert a protective role against cardiac dysfunction and hypertrophy by decreasing the expression level of galectin-3. The methodology suggested in this study provides a novel therapeutic strategy against cardiac hypertrophy.


Assuntos
Cardiomegalia/genética , Galectina 3/genética , MicroRNAs/genética , Miócitos Cardíacos/patologia , Animais , Cardiomegalia/patologia , Células Cultivadas , Regulação para Baixo , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Regulação para Cima
13.
Nat Commun ; 11(1): 2551, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439985

RESUMO

Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show that Dio2 is a direct transcriptional target of FoxO1, and the FoxO1-Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restricted FoxO1 knockout mice, we unveil an essential role for the FoxO1-Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1-Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.


Assuntos
Proteína Forkhead Box O1/metabolismo , Iodeto Peroxidase/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Hormônios Tireóideos/metabolismo , Animais , Animais Recém-Nascidos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Iodeto Peroxidase/antagonistas & inibidores , Iodeto Peroxidase/genética , Camundongos , Camundongos Knockout , Ratos , Transdução de Sinais , Remodelação Ventricular
14.
Mol Cell Biol ; 40(14)2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32341082

RESUMO

Pathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompanied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor b (P-TEFb), which is recruited to target genes by the bromodomain protein Brd4 or the super elongation complex (SEC). Here, we describe GPCR-specific regulation of these P-TEFb complexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomyocytes. The SEC was required for the hypertrophic response downstream of either the α1-adrenergic receptor (α1-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the α1-AR response. This was corroborated by the finding that the activation of α1-AR, but not ETR, increased Brd4 occupancy at promoters and superenhancers of hypertrophic genes. Transcriptome analysis demonstrated that the activation of both receptors initiated similar gene expression programs, but that Brd4 inhibition attenuated hypertrophic genes more robustly following α1-AR activation. Finally, we show that protein kinase A (PKA) is required for α1-AR stimulation of Brd4 chromatin occupancy. The differential role of the Brd4/P-TEFb complex in response to distinct GPCR pathways has potential clinical implications, as therapies targeting this complex are currently being explored for heart failure.


Assuntos
Cardiomegalia/metabolismo , Quinase 9 Dependente de Ciclina/metabolismo , Miócitos Cardíacos/metabolismo , Fator B de Elongação Transcricional Positiva/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Cardiomegalia/patologia , Células Cultivadas , Miócitos Cardíacos/patologia , Proteínas Nucleares/metabolismo , Subunidades Proteicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Endotelina/metabolismo , Fatores de Transcrição/metabolismo
15.
Sci Rep ; 10(1): 6652, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313043

RESUMO

The role of Mesenchymal-endothelial transition (MEndoT) in cardiac hypertrophy is unclear. To determine the difference between MEndoT-derived and coronary endothelial cells is essential for understanding the revascularizing strategy in cardiac repair. Using lineage tracing we demonstrated that MEndoT-derived cells exhibit highly heterogeneous which were characterized with highly expression of endothelial markers such as vascular endothelial cadherin(VECAD) and occludin but low expression of Tek receptor tyrosine kinase(Tek), isolectin B4, endothelial nitric oxide synthase(eNOS), von Willebrand factor(vWF), and CD31 after cardiac hypertrophy. RNA-sequencing showed altered expression of fibroblast lineage commitment genes in fibroblasts undergoing MEndoT. Compared with fibroblasts, the expression of p53 and most endothelial lineage commitment genes were upregulated in MEndoT-derived cells; however, the further analysis indicated that MEndoT-derived cells may represent an endothelial-like cell sub-population. Loss and gain function study demonstrated that MEndoT-derived cells are substantial sources of neovascularization, which can be manipulated to attenuate cardiac hypertrophy and preserve cardiac function by improving the expression of endothelial markers in MEndoT-derived cells. Moreover, fibroblasts undergoing MEndoT showed significantly upregulated anti-hypertrophic factors and downregulated pro-hypertrophic factors. Therefore MEndoT-derived cells are an endothelial-like cell population that can be regulated to treat cardiac hypertrophy by improving neovascularization and altering the paracrine effect of fibroblasts.


Assuntos
Cardiomegalia/genética , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , Neovascularização Fisiológica/genética , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Linhagem da Célula/genética , Rastreamento de Células , Transdiferenciação Celular/genética , Modelos Animais de Doenças , Células Endoteliais/patologia , Fibroblastos/patologia , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lectinas/genética , Lectinas/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ocludina/genética , Ocludina/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Transdução de Sinais , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo
16.
Biochem Biophys Res Commun ; 526(4): 960-966, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32303334

RESUMO

Intracellular calcium is related to cardiac hypertrophy. The CaV1.2 channel and Ca2+/calmodulin-dependent protein kinase II (CaMKII) and CaM regulate the intracellular calcium content. However, the differences in CaMKII and CaM in cardiac hypertrophy are still conflicting and are worthy of studying as drug targets. Therefore, in this study, we aim to investigate the roles and mechanism of CaM and CaMKII on CaV1.2 in pathological myocardial hypertrophy. The results showed that ISO stimulation caused SD rat heart and cardiomyocyte hypertrophy. In vivo, the HW/BW, LVW/BW, cross-sectional area, fibrosis ratio and ANP expression were all increased. There were no differences in CaV1.2 channel expression in the in vivo model or the in vitro model, but the ISO stimulation induced channel activity, and the [Ca2+]i increased. The protein expression levels of CaMKII and p-CaMKII were all increased in the ISO group, but the CaM expression level decreased. AIP inhibited ANP, CaMKII and p-CaMKII expression, and ISO-induced [Ca2+]i increased. AIP also reduced HDAC4, p-HDAC and MEF2C expression. However, CMZ did not play a cardiac hypertrophy reversal role in vitro. In conclusion, we considered that compared with CaM, CaMKII may be a much more important drug target in cardiac hypertrophy reversal.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Animais , Canais de Cálcio Tipo L/metabolismo , Cardiomegalia/patologia , Modelos Animais de Doenças , Histona Desacetilases/metabolismo , Isoproterenol , Fatores de Transcrição MEF2/metabolismo , Masculino , Fosforilação , Ratos Sprague-Dawley
17.
Sci Rep ; 10(1): 7172, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32346115

RESUMO

Curcumin is a naturally occurring p300-histone acetyltransferase (p300-HAT) inhibitor that suppresses cardiomyocyte hypertrophy and the development of heart failure in experimental animal models. To enhance the therapeutic potential of curcumin against heart failure, we produced a series of synthetic curcumin analogues and investigated their inhibitory activity against p300-HAT. The compound with the strongest activity was further evaluated to determine its effects on cardiomyocyte hypertrophy and pressure overload-induced heart failure in mice. We synthesised five synthetic curcumin analogues and found that a compound we have named GO-Y030 most strongly inhibited p300-HAT activity. Furthermore, 1 µM GO-Y030, in a manner equivalent to 10 µM curcumin, suppressed phenylephrine-induced hypertrophic responses in cultured cardiomyocytes. In mice undergoing transverse aortic constriction surgery, administration of GO-Y030 at a mere 1% of an equivalently-effective dose of curcumin significantly attenuated cardiac hypertrophy and systolic dysfunction. In addition, this low dose of GO-Y030 almost completely blocked histone H3K9 acetylation and eliminated left ventricular fibrosis. A low dose of the synthetic curcumin analogue GO-Y030 effectively inhibits p300-HAT activity and markedly suppresses the development of heart failure in mice.


Assuntos
Cardiomegalia , Curcumina/análogos & derivados , Insuficiência Cardíaca , Miócitos Cardíacos , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Curcumina/síntese química , Curcumina/química , Curcumina/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley
18.
Int J Nanomedicine ; 15: 1321-1333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161461

RESUMO

Introduction: Currently, the unsatisfactory treatment of cardiac hypertrophy is due to the unbridled myocardial fibrosis. Melatonin has been demonstrated to ameliorate cardiac hypertrophy and its accompanied fibrosis in previous studies. But it is not clinically appealing due to its short-lasting time against the hostile microenvironment when administered orally. Methods: Herein, to address this, poly (lactide) polycarboxybetaine (PLGA-COOH) accompanied by cardiac homing peptide (CHP) and superparamagnetic iron oxide nanoparticles (SPIONs) were used to establish a novel drug delivery and transportation strategy for melatonin via a facile two-step emulsion method. This study characterized these nanoparticles (CHP-mel@SPIONs) and tested their delivery to the hypertrophied heart and their effect on myocardial hypertrophy and fibrosis in an animal model of pressure overload-induced cardiac hypertrophy. Results: The engineered magnetic nanoparticles of CHP-mel@SPIONs were spherical (diameter = 221 ± 13 nm) and had a negative zeta potential of -19.18 ± 3.27 mV. The CHP-mel@SPIONs displayed excellent drug encapsulation capacities of SPIONs (75.27 ± 3.1%) and melatonin (77.69 ± 6.04%) separately, and their magnetic properties were characterized by constructing magnetic hysteresis curves and exhibited no remnant magnetization or coercivity. The animal experiments showed that compared with mel@SPIONs, CHP-mel@SPIONs accumulated more in the heart, especially in the presence of an external magnetic field, with in vivo echocardiography and RT-PCR and histological assessments confirming the amelioration of the myocardial hypertrophy and fibrosis with low drug doses. Conclusion: This simple biocompatible dual-targeting nanoagent may be a potential candidate for the guided clinical therapy of heart disease.


Assuntos
Cardiomegalia/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas de Magnetita/química , Melatonina/administração & dosagem , Miocárdio/patologia , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Óxido Ferroso-Férrico/química , Fibrose , Coração/efeitos dos fármacos , Campos Magnéticos , Melatonina/farmacologia , Nanoestruturas , Peptídeos/química , Pressão , Ratos Sprague-Dawley
20.
Vet Radiol Ultrasound ; 61(3): 291-301, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173960

RESUMO

Radiography is a standard diagnostic test for characterizing left heart enlargement in dogs however limited information is available on the effects of respiratory phases. This prospective and retrospective method comparison study investigated the respiratory effect on the size and shape of the left heart in dogs to determine the usefulness of expiratory radiographs to detect enlargements in the left atrium (LA) and left ventricle (LV). Thoracic radiographs taken at full inspiration and expiration were evaluated in 20 normal beagles and 100 dogs diagnosed with mitral regurgitation (MR). Vertebral heart score (VHS), vertebral left atrial size, elevation of the carina, and dorsal bulging of LA on lateral view and lateral bulging of the left auricular appendage and LV on ventrodorsal view were assessed. In normal dogs, there were no significant differences in the evaluative factors between inspiration and expiration. In dogs with MR, VHS did not change according to respiration. However, bulging of the LA, left auricular appendage, and LV had sharp margin during expiration compared with inspiration. The expiratory radiographic finding of LA bulging had a higher correlation with the LA to aorta ratio compared with LA bulging in the inspiratory radiography. Using a LA to aorta echocardiographic ratio greater than 1.5 as the gold standard, the radiographic sensitivity for LA enlargement was higher during expiration than inspiration. These findings of our study indicated that expiratory radiography can be helpful to support the detection of left heart enlargement, although it can overestimate LA enlargement in dogs with MR.


Assuntos
Cardiomegalia/veterinária , Doenças do Cão/diagnóstico por imagem , Átrios do Coração/diagnóstico por imagem , Insuficiência da Valva Mitral/veterinária , Radiografia/veterinária , Animais , Aorta/diagnóstico por imagem , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/patologia , Doenças do Cão/patologia , Cães , Ecocardiografia/veterinária , Feminino , Átrios do Coração/patologia , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem , Estudos Prospectivos , Radiografia/métodos , Estudos Retrospectivos
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