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1.
Int J Biol Sci ; 20(5): 1815-1832, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481817

RESUMO

Chronic pressure overload can cause pathological cardiac remodeling and eventually heart failure. The ubiquitin specific protease (USP) family proteins play a prominent role in regulating substrate protein degradation and cardiac structural and functional homeostasis. Although USP38 is expressed in the heart, uncertainty exists regarding the function of USP38 in pathological cardiac remodeling. We constructed and generated cardiac specific USP38 knockout mice and cardiac specific USP38 overexpression mice to assess the role of USP38 in pathological cardiac remodeling. Furthermore, we used co-immunoprecipitation (Co-IP) assays and western blot analysis to identify the molecular interaction events. Here, we reported that the expression of USP38 is significantly elevated under a hypertrophic condition in vivo and in vitro. USP38 deletion significantly mitigates cardiomyocyte enlargement in vitro and hypertrophic effect induced by pressure overload, while overexpression of USP38 markedly aggravates cardiac hypertrophy and remodeling. Mechanistically, USP38 interacts with TANK-binding kinase 1 (TBK1) and removes K48-linked polyubiquitination of TBK1, stabilizing p-TBK1 and promoting the activation of its downstream mediators. Overexpression of TBK1 in the heart of cardiac specific USP38 knockout mice partially counteracts the benefit of USP38 deletion on pathological cardiac remodeling. The TBK1 inhibitor Amlexanox significantly alleviates pressure overload induced-cardiac hypertrophy and myocardial fibrosis in mice with USP38 overexpression. Our results demonstrate that USP38 serves as a positive regulator of pathological cardiac remodeling and suggest that targeting the USP38-TBK1 axis is a promising treatment strategy for hypertrophic heart failure.


Assuntos
Insuficiência Cardíaca , Transdução de Sinais , Animais , Camundongos , Cardiomegalia/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Remodelação Ventricular/genética
2.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473855

RESUMO

In order to determine the behavior of the right ventricle, we have reviewed the existing literature in the area of cardiac remodeling, signal transduction pathways, subcellular mechanisms, ß-adrenoreceptor-adenylyl cyclase system and myocardial catecholamine content during the development of left ventricular failure due to myocardial infarction. The right ventricle exhibited adaptive cardiac hypertrophy due to increases in different signal transduction pathways involving the activation of protein kinase C, phospholipase C and protein kinase A systems by elevated levels of vasoactive hormones such as catecholamines and angiotensin II in the circulation at early and moderate stages of heart failure. An increase in the sarcoplasmic reticulum Ca2+ transport without any changes in myofibrillar Ca2+-stimulated ATPase was observed in the right ventricle at early and moderate stages of heart failure. On the other hand, the right ventricle showed maladaptive cardiac hypertrophy at the severe stages of heart failure due to myocardial infarction. The upregulation and downregulation of ß-adrenoreceptor-mediated signal transduction pathways were observed in the right ventricle at moderate and late stages of heart failure, respectively. The catalytic activity of adenylate cyclase, as well as the regulation of this enzyme by Gs proteins, were seen to be augmented in the hypertrophied right ventricle at early, moderate and severe stages of heart failure. Furthermore, catecholamine stores and catecholamine uptake in the right ventricle were also affected as a consequence of changes in the sympathetic nervous system at different stages of heart failure. It is suggested that the hypertrophied right ventricle may serve as a compensatory mechanism to the left ventricle during the development of early and moderate stages of heart failure.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Ventrículos do Coração/metabolismo , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Cardiomegalia/metabolismo , Miocárdio/metabolismo , Receptores Adrenérgicos beta/metabolismo , Catecolaminas/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Adenilil Ciclases/metabolismo
3.
Int J Mol Sci ; 25(5)2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38473911

RESUMO

Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.


Assuntos
Insuficiência Cardíaca , Doenças Mitocondriais , Humanos , Mitocôndrias Cardíacas/metabolismo , Insuficiência Cardíaca/metabolismo , Cardiomegalia/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Doenças Mitocondriais/metabolismo
4.
Nutrients ; 16(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474873

RESUMO

Endocardial endothelium (EE) is a layer of cells covering the cardiac cavities and modulates cardiomyocyte function. This cell type releases several cardioactive factors, including Angiotensin II (Ang II). This octopeptide is known to induce cardiac hypertrophy. However, whether this circulating factor also induces EE hypertrophy is not known. Taurine is known to prevent cardiac hypertrophy. Whether this endogenous antioxidant prevents the effect of Ang II on human EE (hEE) will be verified. Using quantitative fluorescent probe imaging for calcium and reactive oxygen species (ROS), our results show that Ang II induces (10-7 M, 48 h treatment) an increase in hEE cell (hEEC) volume and its nucleus. Pretreatment with 20 mM of taurine prevents morphological remodeling and increases intracellular calcium and ROS. These results suggest that the reported Ang II induces cardiac hypertrophy is associated with hEEC hypertrophy. This later effect is prevented by taurine by reducing intracellular calcium and ROS overloads. Thus, taurine could be an excellent tool for preventing Ang II-induced remodeling of hEECs.


Assuntos
Angiotensina II , Cálcio , Humanos , Espécies Reativas de Oxigênio/metabolismo , Angiotensina II/metabolismo , Cálcio/metabolismo , Taurina/farmacologia , Cardiomegalia/metabolismo , Miócitos Cardíacos , Endotélio/metabolismo
5.
Sci Rep ; 14(1): 5695, 2024 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459104

RESUMO

The successful integration of neural networks in a clinical setting is still uncommon despite major successes achieved by artificial intelligence in other domains. This is mainly due to the black box characteristic of most optimized models and the undetermined generalization ability of the trained architectures. The current work tackles both issues in the radiology domain by focusing on developing an effective and interpretable cardiomegaly detection architecture based on segmentation models. The architecture consists of two distinct neural networks performing the segmentation of both cardiac and thoracic areas of a radiograph. The respective segmentation outputs are subsequently used to estimate the cardiothoracic ratio, and the corresponding radiograph is classified as a case of cardiomegaly based on a given threshold. Due to the scarcity of pixel-level labeled chest radiographs, both segmentation models are optimized in a semi-supervised manner. This results in a significant reduction in the costs of manual annotation. The resulting segmentation outputs significantly improve the interpretability of the architecture's final classification results. The generalization ability of the architecture is assessed in a cross-domain setting. The assessment shows the effectiveness of the semi-supervised optimization of the segmentation models and the robustness of the ensuing classification architecture.


Assuntos
Inteligência Artificial , Cardiomegalia , Humanos , Cardiomegalia/diagnóstico por imagem , Generalização Psicológica , Coração , Processamento de Imagem Assistida por Computador , Redes Neurais de Computação
7.
J Int Med Res ; 52(3): 3000605241233524, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38497134

RESUMO

OBJECTIVE: To develop an experimental porcine model of tricuspid regurgitation using two induction routes: the inferior vena cava and superior vena cava. METHODS: Tricuspid regurgitation was generated using the loop wire cutting method. The tricuspid regurgitation jet direction was controlled by accessing the valve through the inferior (n = 7) or superior (n = 6) vena cava. The occurrence, direction, and progression of tricuspid regurgitation were assessed postoperatively, and echocardiography was performed at 4 to 6 weeks. Right heart dilatation was assessed using computed tomography after 6 weeks. RESULTS: Moderate to severe or torrential tricuspid regurgitation occurred immediately after the procedure in 12 of 13 animals. The jet was directed toward the septum in five of seven animals in the inferior vena cava group and toward the posterolateral side in four of six animals in the superior vena cava group. The dimensions of the right heart (right atrium, ventricle, and tricuspid valve annulus) were significantly enlarged at the 4- to 6-week follow-up echocardiographic examination and confirmed to be enlarged by computed tomography, independent of the route used. CONCLUSION: The loop wire cutting method successfully induced a disease model of tricuspid regurgitation while controlling the regurgitation jet direction via two procedural routes.


Assuntos
Insuficiência da Valva Tricúspide , Suínos , Animais , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/cirurgia , Veia Cava Superior , Átrios do Coração/diagnóstico por imagem , Ecocardiografia , Cardiomegalia
8.
Ann Clin Lab Sci ; 54(1): 17-25, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38514055

RESUMO

OBJECTIVE: Diabetic cardiomyopathy (DCM) is the most common cardiovascular complication of type 2 diabetes mellitus (T2DM). Patients affected with DCM face a notably higher risk of progressing to congestive heart failure compared to other populations. Myocardial hypertrophy, a clearly confirmed pathological change in DCM, plays an important role in the development of DCM, with abnormal Ca2+ homeostasis serving as the key signal to induce myocardial hypertrophy. Therefore, investigating the mechanism of Ca2+ transport is of great significance for the prevention and treatment of myocardial hypertrophy in T2DM. METHODS: The rats included in the experiment were divided into wild type (WT) group and T2DM group. The T2DM rat model was established by feeding the rats with high-fat and high-sugar diets for three months combined with low dose of streptozotocin (100mg/kg). Afterwards, primary rat cardiomyocytes were isolated and cultured, and cardiomyocyte hypertrophy was induced through high-glucose treatment. Subsequently, mechanistic investigations were carried out through transfection with si-STIM1 and oe-STIM1. Western blot (WB) was used to detect the expression of the STIM1, Orai1 and p-CaMKII. qRT-PCR was used to detect mRNA levels of myocardial hypertrophy marker proteins. Cell surface area was detected using TRITC-Phalloidin staining, and intracellular Ca2+ concentration in cardiomyocytes was measured using Fluo-4 fluorescence staining. RESULTS: Through animal experiments, an upregulation of Orai1 and STIM1 was revealed in the rat model of myocardial hypertrophy induced by T2DM. Meanwhile, through cell experiments, it was found that in high glucose (HG)-induced hypertrophic cardiomyocytes, the expression of STIM1, Orai1, and p-CaMKII was upregulated, along with increased levels of store-operated Ca2+ entry (SOCE) and abnormal Ca2+ homeostasis. However, when STIM1 was downregulated in HG-induced cardiomyocytes, SOCE levels decreased and p-CaMKII was downregulated, resulting in an improvement in myocardial hypertrophy. To further elucidate the mechanism of action involving SOCE and CaMKII in T2DM-induced myocardial hypertrophy, high-glucose cardiomyocytes were respectively treated with BTP2 (SOCE blocker) and KN-93 (CaMKII inhibitor), and the results showed that STIM1 can mediate SOCE, thereby affecting the phosphorylation level of CaMKII and improving cardiomyocyte hypertrophy. CONCLUSION: STIM1/Orai1-mediated SOCE regulates p-CaMKII levels, thereby inducing myocardial hypertrophy in T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Ratos , Animais , Diabetes Mellitus Tipo 2/complicações , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Regulação para Cima , Cardiomegalia , Glucose , Cálcio/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo
9.
Mol Med Rep ; 29(5)2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38456539

RESUMO

Cardiac hypertrophy is one of the key processes in the development of heart failure. Notably, small GTPases and GTPase­activating proteins (GAPs) serve essential roles in cardiac hypertrophy. RhoGAP interacting with CIP4 homologs protein 1 (RICH1) is a RhoGAP that can regulate Cdc42/Rac1 and F­actin dynamics. RICH1 is involved in cell proliferation and adhesion; however, to the best of our knowledge, its role in cardiac hypertrophy remains unknown. In the present study, the role of RICH1 in cardiomyocyte hypertrophy was assessed. Cell viability was analyzed using the Cell Counting Kit­8 assay and cells surface area (CSA) was determined by cell fluorescence staining. Reverse transcription­quantitative PCR and western blotting were used to assess the mRNA expression levels of hypertrophic marker genes, such as Nppa, Nppb and Myh7, and the protein expression levels of RICH1, respectively. RICH1 was shown to be downregulated in isoproterenol (ISO)­ or angiotensin II (Ang II)­treated H9c2 cells. Notably, overexpression of RICH1 attenuated the upregulation of hypertrophy­related markers, such as Nppa, Nppb and Myh7, and the enlargement of CSA induced by ISO and Ang II. By contrast, the knockdown of RICH1 exacerbated these effects. These findings suggested that RICH1 may be a novel suppressor of ISO­ or Ang II­induced cardiomyocyte hypertrophy. The results of the present study will be beneficial to further studies assessing the role of RICH1 and its downstream molecules in inhibiting cardiac hypertrophy.


Assuntos
Cardiopatias Congênitas , Miócitos Cardíacos , Nitrobenzoatos , Procainamida/análogos & derivados , Humanos , Miócitos Cardíacos/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Isoproterenol/farmacologia , Isoproterenol/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiopatias Congênitas/metabolismo
10.
Nat Commun ; 15(1): 2358, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509128

RESUMO

While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.


Assuntos
Insuficiência Cardíaca , Estresse Oxidativo , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Oxirredução , Insuficiência Cardíaca/genética , Cardiomegalia , Epigênese Genética , Isocitrato Desidrogenase/genética
11.
Drug Des Devel Ther ; 18: 781-799, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38500692

RESUMO

Purpose: This study aimed to elucidate the protective mechanism of Traditional Chinese Medicine (TCM) Qifu Yixin formula (QFYXF) to improve heart failure (HF) by promoting ß-arrestin2 (ß-arr2)-mediated SERCA2a SUMOylation. Materials and Methods: The transverse aortic constriction (TAC)-induced HF mice were treated with QFYXF or carvedilol for 8 weeks. ß-arr2-KO mice and their littermate wild-type (WT) mice were used as controls. Neonatal rat cardiomyocytes (NRCMs) were used in vitro. Cardiac function was evaluated by echocardiography and serum NT-proBNP. Myocardial hypertrophy and myocardial fibrosis were assessed by histological staining. ß-arr2, SERCA2a, SUMO1, PLB and p-PLB expressions were detected by Western blotting, immunofluorescence and immunohistochemistry. SERCA2a SUMOylation was detected by Co-IP. The molecular docking method was used to predict the binding ability of the main active components of QFYXF to ß-arr2, SERCA2a, and SUMO1, and the binding degree of SERCA2a to SUMO1 protein. Results: The HF model was constructed 8 weeks after TAC. QFYXF ameliorated cardiac function, inhibiting myocardial hypertrophy and fibrosis. QFYXF promoted SERCA2a expression and SERCA2a SUMOylation. Further investigation showed that QFYXF promoted ß-arr2 expression, whereas Barbadin (ß-arr2 inhibitor) or ß-arr2-KO reduced SERCA2a SUMOylation and attenuated the protective effect of QFYXF improved HF. Molecular docking showed that the main active components of QFYXF had good binding activities with ß-arr2, SERCA2a, and SUMO1, and SERCA2a had a high binding degree with SUMO1 protein. Conclusion: QFYXF improves HF by promoting ß-arr2 mediated SERCA2a SUMOylation and increasing SERCA2a expression.


Assuntos
Insuficiência Cardíaca , Sumoilação , Ratos , Camundongos , Animais , Simulação de Acoplamento Molecular , Miócitos Cardíacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo
12.
Front Endocrinol (Lausanne) ; 15: 1339741, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455657

RESUMO

Introduction: Thyroid hormones (THs) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases is still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Methods: Mice at the age of 12 months underwent TAC and received T4 or anti-thyroid medication in drinking water over the course of 4 weeks after induction of left ventricular pressure overload. Results: T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis, and interstitial fibrosis), and mortality. This is surprising because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. Comparing the gene expression of deiodinases (Dio) 2 and 3 and TH receptor alpha (TRα) 1 and the dominant-negative acting isoform TRα2 between young and aged mice revealed that aged mice exhibited a higher expression of TRα2 and Dio3, while expression of Dio2 was reduced compared with young mice. These changes in Dio2 and 3 expressions might lead to reduced TH availability in the hearts of 12-month-old mice accompanied by reduced TRα action due to higher TRα2. Discussion: In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure-induced cardiac damage. This observation seems to be the result of an altered expression of deiodinases and TRα isoforms, thus suggesting that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.


Assuntos
Insuficiência Cardíaca , Hipertensão , Camundongos , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Insuficiência Cardíaca/etiologia , Miócitos Cardíacos/metabolismo , Hormônios Tireóideos/metabolismo , Hipertensão/complicações
13.
Biomed Pharmacother ; 172: 116241, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38330711

RESUMO

OBJECTIVE: Pathologic cardiac hypertrophy (PCH) is a precursor to heart failure. Amydrium sinense (Engl.) H. Li (AS), a traditional Chinese medicinal plant, has been extensively utilized to treat chronic inflammatory diseases. However, the therapeutic effect of ASWE on PCH and its underlying mechanisms are still not fully understood. METHODS: A cardiac hypertrophy model was established by treating C57BL/6 J mice and neonatal rat cardiomyocytes (NRCMs) in vitro with isoprenaline (ISO) in this study. The antihypertrophic effects of AS water extract (ASWE) on cardiac function, histopathologic manifestations, cell surface area and expression levels of hypertrophic biomarkers were examined. Subsequently, the impact of ASWE on inflammatory factors, p65 nuclear translocation and NF-κB activation was investigated to elucidate the underlying mechanisms. RESULTS: In the present study, we observed that oral administration of ASWE effectively improved ISO-induced cardiac hypertrophy in mice, as evidenced by histopathological manifestations and the expression levels of hypertrophic markers. Furthermore, the in vitro experiments demonstrated that ASWE treatment inhibited cardiac hypertrophy and suppressed inflammation response in ISO-treated NRCMs. Mechanically, our findings provided evidence that ASWE suppressed inflammation response by repressing p65 nuclear translocation and NF-κB activation. ASWE was found to possess the capability of inhibiting inflammation response and cardiac hypertrophy induced by ISO. CONCLUSION: To sum up, ASWE treatment was shown to attenuate ISO-induced cardiac hypertrophy by inhibiting cardiac inflammation via preventing the activation of the NF-kB signaling pathway. These findings provided scientific evidence for the development of ASWE as a novel therapeutic drug for PCH treatment.


Assuntos
Araceae , NF-kappa B , Animais , Camundongos , Ratos , Camundongos Endogâmicos C57BL , Isoproterenol/toxicidade , Transdução de Sinais , Íons , Lítio , Artesunato , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico
14.
Life Sci ; 341: 122482, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38309577

RESUMO

AIMS: RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that regulates heart failure. This study aims to unravel a new biological function of RBM10 phosphorylation by proto-oncogene cSrc that enables anti-hypertrophy gene program and controls cardiac hypertrophy. MATERIALS AND METHODS: We employ in vitro and in vivo approaches to characterise RBM10 phosphorylation at three-tyrosine residues (Y81, Y500, and Y971) by cSrc and target mRNA regulation. We also use isoproterenol induced rat heart and cellular hypertrophy model to determine role of cSrc-mediated RBM10 phosphorylation. KEY FINDINGS: We show that RBM10 phosphorylation is induced in cellular and animal heart model of cardiac hypertrophy and regulates target mRNA expression and 3'-end formation. Inhibition of cSrc kinase or mutation of the three-tyrosine phosphorylation sites to phenylalanine accentuates myocyte hypertrophy, and results in advancement and an early attainment of hypertrophy in the heart. RBM10 is down regulated in the hypertrophic myocyte and that its re-expression reverses cellular and molecular changes in the myocyte. However, in the absence of phosphorylation (cSrc inhibition or phospho-deficient mutation), restoration of endogenous RBM10 level in the hypertrophic heart or ectopic re-expression in vitro failed to reverse cardiomyocyte hypertrophy. Mechanistically, loss of RBM10 phosphorylation inhibits nuclear localisation and interaction with Star-PAP compromising anti-hypertrophy gene expression. SIGNIFICANCE: Our study establishes that cSrc-mediated RBM10 phosphorylation arbitrates anti-hypertrophy gene program. We also report a new functional regulation of RBM10 by phosphorylation that is poised to control heart failure.


Assuntos
Cardiomegalia , Insuficiência Cardíaca , Ratos , Animais , Fosforilação , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Proto-Oncogenes , RNA Mensageiro/genética , Tirosina/metabolismo , Miócitos Cardíacos/metabolismo
15.
Int J Mol Sci ; 25(4)2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38397020

RESUMO

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC50 of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy.


Assuntos
Anserina , Cardiomiopatias , Insuficiência Cardíaca , Miócitos Cardíacos , Fatores de Transcrição de p300-CBP , Animais , Humanos , Masculino , Camundongos , Acetilação , Anserina/farmacologia , Cardiomegalia/genética , Cardiomiopatias/metabolismo , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/metabolismo , Histonas/metabolismo , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fenilefrina/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores
16.
Int J Mol Sci ; 25(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38397106

RESUMO

Hypertension is the key contributor to pathological cardiac hypertrophy. Growing evidence indicates that glucose metabolism plays an essential role in cardiac hypertrophy. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism in pressure overload-induced cardiac remodeling. In the present study, we investigated the role of TIGAR in cardiac remodeling during Angiotensin II (Ang-II)-induced hypertension. Wild-type (WT) and TIGAR knockout (KO) mice were infused with Angiotensin-II (Ang-II, 1 µg/kg/min) via mini-pump for four weeks. The blood pressure was similar between the WT and TIGAR KO mice. The Ang-II infusion resulted in a similar reduction of systolic function in both groups, as evidenced by the comparable decrease in LV ejection fraction and fractional shortening. The Ang-II infusion also increased the isovolumic relaxation time and myocardial performance index to the same extent in WT and TIGAR KO mice, suggesting the development of similar diastolic dysfunction. However, the knockout of TIGAR significantly attenuated hypertension-induced cardiac hypertrophy. This was associated with higher levels of fructose 2,6-bisphosphate, PFK-1, and Glut-4 in the TIGAR KO mice. Our present study suggests that TIGAR is involved in the control of glucose metabolism and glucose transporters by Ang-II and that knockout of TIGAR attenuates the development of maladaptive cardiac hypertrophy.


Assuntos
Angiotensina II , Proteínas Reguladoras de Apoptose , Cardiomegalia , Hipertensão , Animais , Camundongos , Angiotensina II/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomegalia/genética , Cardiomegalia/induzido quimicamente , Fibrose , Glucose/metabolismo , Glicólise , Hipertensão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Remodelação Ventricular/fisiologia
17.
Nat Commun ; 15(1): 1347, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355644

RESUMO

Accurate identification and localization of multiple abnormalities are crucial steps in the interpretation of chest X-rays (CXRs); however, the lack of a large CXR dataset with bounding boxes severely constrains accurate localization research based on deep learning. We created a large CXR dataset named CXR-AL14, containing 165,988 CXRs and 253,844 bounding boxes. On the basis of this dataset, a deep-learning-based framework was developed to identify and localize 14 common abnormalities and calculate the cardiothoracic ratio (CTR) simultaneously. The mean average precision values obtained by the model for 14 abnormalities reached 0.572-0.631 with an intersection-over-union threshold of 0.5, and the intraclass correlation coefficient of the CTR algorithm exceeded 0.95 on the held-out, multicentre and prospective test datasets. This framework shows an excellent performance, good generalization ability and strong clinical applicability, which is superior to senior radiologists and suitable for routine clinical settings.


Assuntos
Anormalidades Múltiplas , Aprendizado Profundo , Humanos , Estudos Prospectivos , Raios X , Cardiomegalia/diagnóstico por imagem
18.
Molecules ; 29(4)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38398512

RESUMO

Cardiac hypertrophy (CH) is an important characteristic in heart failure development. Chlorogenic acid (CGA), a crucial bioactive compound from honeysuckle, is reported to protect against CH. However, its underlying mechanism of action remains incompletely elucidated. Therefore, this study aimed to explore the mechanism underlying the protective effect of CGA on CH. This study established a CH model by stimulating AC16 cells with isoproterenol (Iso). The observed significant decrease in cell surface area, evaluated through fluorescence staining, along with the downregulation of CH-related markers, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and ß-myosin heavy chain (ß-MHC) at both mRNA and protein levels, provide compelling evidence of the protective effect of CGA against isoproterenol-induced CH. Mechanistically, CGA induced the expression of glycogen synthase kinase 3ß (GSK-3ß) while concurrently attenuating the expression of the core protein ß-catenin in the Wnt/ß-catenin signaling pathway. Furthermore, the experiment utilized the Wnt signaling activator IM-12 to observe its ability to modulate the impact of CGA pretreatment on the development of CH. Using the Gene Expression Omnibus (GEO) database combined with online platforms and tools, this study identified Wnt-related genes influenced by CGA in hypertrophic cardiomyopathy (HCM) and further validated the correlation between CGA and the Wnt/ß-catenin signaling pathway in CH. This result provides new insights into the molecular mechanisms underlying the protective effect of CGA against CH, indicating CGA as a promising candidate for the prevention and treatment of heart diseases.


Assuntos
Ácido Clorogênico , Via de Sinalização Wnt , Humanos , Isoproterenol/toxicidade , Ácido Clorogênico/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , beta Catenina/metabolismo
19.
Int Immunopharmacol ; 129: 111660, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38350357

RESUMO

BACKGROUND: Human amniotic mesenchymal stem cells (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammation which makes them suitable for the treatment of various diseases. OBJECTIVE: This study aimed to explore the therapeutic effect and molecular mechanism of hAMSCs in ventricular remodeling (VR). METHODS: hAMSCs were characterized by a series of experiments such as flow cytometric analysis, immunofluorescence, differentiative induction and tumorigenicity. Mouse VR model was induced by isoproterenol (ISO) peritoneally, and the therapeutic effects and the potential mechanisms of hAMSCs transplantation were evaluated by echocardiography, carboxy fluorescein diacetate succinimidyl ester (CFSE) labeled cell tracing, histochemistry, qRT-PCR and western blot analysis. The co-culturing experiments were carried out for further exploring the mechanisms of hAMSCs-derived conditioned medium (CM) on macrophage polarization and fibroblast fibrosis in vitro. RESULTS: hAMSCs transplantation significantly alleviated ISO-induced VR including cardiac hypertrophy and fibrosis with the improvements of cardiac functions. CFSE labeled hAMSCs kept an undifferentiated state in heart, indicating that hAMSCs-mediated the improvement of ISO-induced VR might be related to their paracrine effects. hAMSCs markedly inhibited ISO-induced inflammation and fibrosis, seen as the increase of M2 macrophage infiltration and the expressions of CD206 and IL-10, and the decreases of CD86, iNOS, COL3 and αSMA expressions in heart, suggesting that hAMSCs transplantation promoted the polarization of M2 macrophages and inhibited the polarization of M1 macrophages. Mechanically, hAMSCs-derived CM significantly increased the expressions of CD206, IL-10, Arg-1 and reduced the expressions of iNOS and IL-6 in RAW264.7 macrophages in vitro. Interestingly, RAW264.7-CM remarkably promoted the expressions of anti-inflammatory factors such as IL-10, IDO, and COX2 in hAMSCs. Furthermore, the CM derived from hAMSCs pretreated with RAW264.7-CM markedly inhibited the expressions of fibrogenesis genes such as αSMA and COL3 in 3T3 cells. CONCLUSION: Our results demonstrated that hAMSCs effectively alleviated ISO-induced cardiac hypertrophy and fibrosis, and improved the cardiac functions in mice, and the underlying mechanisms might be related to inhibiting the inflammation and fibrosis during the ventricular remodeling through promoting the polarization of CD206hiIL-10hi macrophages in heart tissues. Our study strongly suggested that by taking the advantages of the potent immunosuppressive and anti-inflammatory effects, hAMSCs may provide an alternative therapeutic approach for prevention and treatment of VR clinically.


Assuntos
Fluoresceínas , Interleucina-10 , Células-Tronco Mesenquimais , Succinimidas , Camundongos , Humanos , Animais , Interleucina-10/farmacologia , Âmnio , Isoproterenol , Remodelação Ventricular , Macrófagos , Inflamação/induzido quimicamente , Inflamação/terapia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Fibrose , Cardiomegalia
20.
Mol Metab ; 81: 101899, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38346589

RESUMO

OBJECTIVE: Pompe disease (PD) is caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to progressive glycogen accumulation and severe myopathy with progressive muscle weakness. In the Infantile-Onset PD (IOPD), death generally occurs <1 year of age. There is no cure for IOPD. Mouse models of PD do not completely reproduce human IOPD severity. Our main objective was to generate the first IOPD rat model to assess an innovative muscle-directed adeno-associated viral (AAV) vector-mediated gene therapy. METHODS: PD rats were generated by CRISPR/Cas9 technology. The novel highly myotropic bioengineered capsid AAVMYO3 and an optimized muscle-specific promoter in conjunction with a transcriptional cis-regulatory element were used to achieve robust Gaa expression in the entire muscular system. Several metabolic, molecular, histopathological, and functional parameters were measured. RESULTS: PD rats showed early-onset widespread glycogen accumulation, hepato- and cardiomegaly, decreased body and tissue weight, severe impaired muscle function and decreased survival, closely resembling human IOPD. Treatment with AAVMYO3-Gaa vectors resulted in widespread expression of Gaa in muscle throughout the body, normalizing glycogen storage pathology, restoring muscle mass and strength, counteracting cardiomegaly and normalizing survival rate. CONCLUSIONS: This gene therapy holds great potential to treat glycogen metabolism alterations in IOPD. Moreover, the AAV-mediated approach may be exploited for other inherited muscle diseases, which also are limited by the inefficient widespread delivery of therapeutic transgenes throughout the muscular system.


Assuntos
Doença de Depósito de Glicogênio Tipo II , Camundongos , Ratos , Humanos , Animais , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/terapia , Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/metabolismo , Glicogênio/metabolismo , Terapia Genética/métodos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/terapia
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