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Acute myocardial infarction (AMI) is one of the major causes of death worldwide, posing significant global health challenges. Circular RNA (circRNA) has recently emerged as a potential diagnostic biomarker for AMI, providing valuable information for timely medical care. In this work, a new electrochemical method for circRNA detection by engineering a collaborative CRISPR-Cas system is developed. This system integrates the unique circRNA-targeting ability with cascade trans-cleavage activities of Cas effectors, using an isothermal primer exchange reaction as the bridge. Using cZNF292, a circulating circRNA biomarker for AMI is identified by this group; as a model, the collaborative CRISPR-Cas system-based method exhibits excellent accuracy and sensitivity with a low detection limit of 2.13 × 10-15 m. Moreover, the method demonstrates a good diagnostic performance for AMI when analyzing whole blood samples. Therefore, the method may provide new insight into the detection of circRNA biomarkers and is expected to have great potential in AMI diagnosis in the future.
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BACKGROUND: The benefits of exercise training in the cardiovascular system have been well accepted; however, the underlying mechanism remains to be explored. Here, we report the initial functional characterization of an exercise-induced cardiac physiological hypertrophy-associated novel long noncoding RNA (lncRNA). METHODS: Using lncRNA microarray profiling, we identified lncRNAs in contributing the modulation of exercise-induced cardiac growth that we termed cardiac physiological hypertrophy-associated regulator (CPhar). Mice with adeno-associated virus serotype 9 driving CPhar overexpression and knockdown were used in in vivo experiments. Swim training was used to induce physiological cardiac hypertrophy in mice, and ischemia reperfusion injury surgery was conducted to investigate the protective effects of CPhar in mice. To investigate the mechanisms of CPhar's function, we performed various analyses including quantitative reverse transcription polymerase chain reaction, Western blot, histology, cardiac function (by echocardiography), functional rescue experiments, mass spectrometry, in vitro RNA transcription, RNA pulldown, RNA immunoprecipitation, chromatin immunoprecipitation assay, luciferase reporter assay, and coimmunoprecipitation assays. RESULTS: We screened the lncRNAs in contributing the modulation of exercise-induced cardiac growth through lncRNA microarray profiling and found that CPhar was increased with exercise and was necessary for exercise-induced physiological cardiac growth. The gain and loss of function of CPhar regulated the expression of proliferation markers, hypertrophy, and apoptosis in cultured neonatal mouse cardiomyocytes. Overexpression of CPhar prevented myocardial ischemia reperfusion injury and cardiac dysfunction in vivo. We identified DDX17 (DEAD-Box Helicase 17) as a binding partner of CPhar in regulating CPhar downstream factor ATF7 (activating transcription factor 7) by sequestering C/EBPß (CCAAT/enhancer binding protein beta). CONCLUSIONS: Our study of this lncRNA CPhar provides new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of CPhar in the heart, and expanding our mechanistic understanding of lncRNA function, as well.
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Biomarcadores , Cardiomegalia/etiología , Entrenamiento Aeróbico/efectos adversos , Daño por Reperfusión Miocárdica/etiología , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/genética , Recuperación de la Función/genética , Factores de Transcripción Activadores/genética , Factores de Transcripción Activadores/metabolismo , Animales , Apoptosis , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Cardiomegalia/diagnóstico , Modelos Animales de Enfermedad , Ecocardiografía , Perfilación de la Expresión Génica , Ratones , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatologíaRESUMEN
BACKGROUND: Cathelicidins are a major group of natural antimicrobial peptides which play essential roles in regulating host defense and immunity. In addition to the antimicrobial and immunomodulatory activities, recent studies have reported the involvement of cathelicidins in cardiovascular diseases by regulating inflammatory response and microvascular dysfunction. However, the role of cathelicidins in myocardial apoptosis upon cardiac ischemia/reperfusion (I/R) injury remains largely unknown. METHODS: CRAMP (cathelicidin-related antimicrobial peptide) levels were measured in the heart and serum from I/R mice and in neonatal mouse cardiomyocytes treated with oxygen glucose deprivation/reperfusion (OGDR). Human serum cathelicidin antimicrobial peptide (LL-37) levels were measured in myocardial infarction (MI) patients. The role of CRAMP in myocardial apoptosis upon I/R injury was investigated in mice injected with the CRAMP peptide and in CRAMP knockout (KO) mice, as well as in OGDR-treated cardiomyocytes. RESULTS: We observed reduced CRAMP level in both heart and serum samples from I/R mice and in OGDR-treated cardiomyocytes, as well as reduced LL-37 level in MI patients. Knockdown of CRAMP enhanced cardiomyocyte apoptosis, and CRAMP KO mice displayed increased infarct size and myocardial apoptosis. In contrast, the CRAMP peptide reduced cardiomyocyte apoptosis and I/R injury. The CRAMP peptide inhibited cardiomyocyte apoptosis by activation of Akt and ERK1/2 and phosphorylation and nuclear export of FoxO3a. c-Jun was identified as a negative regulator of the CRAMP gene. Moreover, lower level of serum LL-37/neutrophil ratio was associated with readmission and/or death in MI patients during 1-year follow-up. CONCLUSIONS: CRAMP protects against cardiomyocyte apoptosis and cardiac I/R injury via activation of Akt and ERK and phosphorylation and nuclear export of FoxO3a. Increasing LL-37 might be a novel therapy for cardiac ischemic injury.
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Antiinfecciosos/uso terapéutico , Catelicidinas/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Animales , Antiinfecciosos/farmacología , Catelicidinas/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
d-galactose (d-gal)-induced cardiac alterations and Doxorubicin (Dox)-induced cardiomyocyte senescence are commonly used models to study cardiac aging. Accumulating evidence has suggested that microRNAs (miRNAs, miRs) are critically involved in the regulation of cellular and organismal aging and age-related diseases. However, little has been revealed about the roles of miRNAs in cardiac alterations induced by d-gal and Dox. In this study, we used miRNA arrays to investigate the dysregulated miRNAs in heart samples from 15month-old versus 2month-old male C57BL/6 mice and further validated them in d-gal-induced pseudo-aging mouse model and Dox-induced cardiomyocyte senescence in vitro model. We confirmed a significant increase of miR-21 in all these models by quantitative reverse transcription polymerase chain reactions. We further demonstrated that miR-21 was able to promote Dox-induced cardiomyocyte senescence whereas suppression of miR-21 could prevent that, as determined by percentage of ß-gal-positive cells and gene markers of aging. Phosphatase and tensin homolog (PTEN) was identified as a target gene of miR-21, mediating its effect in increasing cardiomyocyte senescence. Finally, we found that miR-21 knockout mice were resistant to d-gal-induced alterations in aging-markers and cardiac function. Collectively, this study provides direct evidence that inhibition of miR-21 is protective against d-gal-induced cardiac alterations and Dox-induced cardiomyocyte senescence via targeting PTEN. Inhibition of miR-21 might be a novel strategy to combat cardiac aging.
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Doxorrubicina/efectos adversos , Galactosa/efectos adversos , MicroARNs/metabolismo , Miocardio/metabolismo , Miocardio/patología , Envejecimiento/patología , Animales , Senescencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosfohidrolasa PTEN/metabolismoRESUMEN
Telocytes (TCs) are a novel type of stromal cells reported by Popescu's group in 2010. The unique feature that distinguishes TCs from other "classical" stromal cells is their extremely long and thin telopodes (Tps). As evidenced by electron microscopy, TCs are widely distributed in almost all tissues and organs. TCs contribute to form a three-dimensional interstitial network and play as active regulators in intercellular communication via homocellular/heterocellular junctions or shed vesicles. Interestingly, increasing evidence suggests the potential role of TCs in regenerative medicine. Although the heart retains some limited endogenous regenerative capacity, cardiac regenerative and repair response is however insufficient to make up the loss of cardiomyocytes upon injury. Developing novel strategies to increase cardiomyocyte renewal and repair is of great importance for the treatment of cardiac diseases. In this review, we focus on the role of TCs in cardiac regeneration and repair. We particularly describe the intercellular communication between TCs and cardiomyocytes, stem/progenitor cells, endothelial cells, and fibroblasts. Also, we discuss the current knowledge about TCs in cardiac repair after myocardial injury, as well as their potential roles in cardiac development and aging. TC-based therapy or TC-derived exosome delivery might be used as novel therapeutic strategies to promote cardiac regeneration and repair.
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Corazón/fisiología , Regeneración/fisiología , Telocitos/citología , Animales , Exosomas/metabolismo , Corazón/crecimiento & desarrollo , Humanos , Uniones Intercelulares/metabolismo , Medicina RegenerativaRESUMEN
Emerging evidence demonstrated that particulate matter 2.5 (PM2.5) is an important environmental risk factor for lung diseases. Serum- and glucocorticoid-inducible kinase 1(SGK1) was reported to be a crucial factor for cell survival. However, the role of SGK1 in PM2.5-induced cell injury is still unclear. In this work, we firstly found that the expression of SGK1 was decreased in PM2.5-treated human lung alveolar epithelial (A549) cells by western blot. In addition, overexpression of SGK1 significantly attenuated A549â¯cell apoptosis and reduced the reactive oxygen species (ROS) generation induced by PM2.5. Moreover, we found that PM2.5 exposure significantly promoted the ERK1/2 activation and inhibited the AKT activation, whereas overexpression of SGK1 could reverse that. Finally, the results of the rescue experiment showed that MK2206 (AKT inhibitor) could rescue the impact of SGK1 on A549â¯cell apoptosis, while PD98059 (ERK1/2 inhibitor) could not further aggravate the impact. Taken together, our results suggest that SGK1 inhibits PM2.5-induced cell apoptosis and ROS generation via ERK1/2 and AKT signaling pathway in human lung alveolar epithelial A549â¯cells.
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Células Epiteliales Alveolares/citología , Células Epiteliales Alveolares/fisiología , Apoptosis/fisiología , Proteínas Inmediatas-Precoces/metabolismo , Estrés Oxidativo/fisiología , Material Particulado/administración & dosificación , Proteínas Serina-Treonina Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Células Epiteliales Alveolares/efectos de los fármacos , Apoptosis/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Cardiovascular diseases are among the most serious diseases, which are a leading cause of death across the world. Early diagnosis and prognosis prediction are keys for treatment and reduction of death rates. Circular RNAs (circRNAs) play a critical role in the physiology and pathology of biological system and participate in the development of diseases. In addition, circRNAs are relative stable and abundant. Therefore, many studies have suggested that circRNAs could be used as biomarkers for diseases, such as neurological diseases, cancers, immune diseases, and digestive diseases. Here we summarize recent studies on circRNAs and compare the characteristics of circRNAs with traditional biomarkers. Finally, we highlight the value of circRNAs as potential biomarkers for cardiovascular diseases, including acute myocardial infarction, heart failure, coronary artery disease, and hypertension. In conclusion, circRNAs may be promising biomarkers for cardiovascular diseases.
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Enfermedades Cardiovasculares/diagnóstico , ARN/análisis , Biomarcadores/análisis , Enfermedades Cardiovasculares/genética , Predicción , Humanos , ARN/genética , ARN/metabolismo , ARN Circular , ARN Largo no Codificante/análisis , ARN Largo no Codificante/metabolismoRESUMEN
Circular RNAs (circRNAs), a group of circular RNA molecules with a 3',5'-phosphodiester bond at the junction site, are generated by back-splicing of precursor mRNAs. Most of the circular RNAs originate from the exon region of the encoded protein, and some are derived from intron regions, antisense transcripts, or long noncoding RNAs. Circular RNAs are abundantly in eukaryotic transcriptome and participate in various biological processes. It is closely associated with various diseases such as tumors, diabetes, nervous system diseases, and cardiovascular diseases. In cardiovascular system, numerous circRNAs have been identified and involved in important processes of cardiovascular development and diseases. Here we will review the latest research progress of circular RNA in cardiovascular diseases. Also, we will outline the specific examples of circRNAs involved in cardiovascular system regulatory effects, including act as miRNA sponges, interaction with RNA-binding proteins, regulated by RNA-binding proteins and serve as biomarkers. In addition, potential mechanisms underlying the regulatory role of circRNAs in cardiovascular diseases will be discussed.
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Enfermedades Cardiovasculares/genética , ARN/genética , Empalme Alternativo , Animales , Líquidos Corporales/química , Enfermedades Cardiovasculares/diagnóstico , Predicción , Regulación de la Expresión Génica/genética , Humanos , MicroARNs/metabolismo , Conformación de Ácido Nucleico , ARN/análisis , ARN/metabolismo , ARN Circular , ARN Largo no Codificante/análisis , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
Denervation, disuse, fasting, and various diseases could induce skeletal muscle atrophy, which results in the decline of life quality and increase of the mortality risk for patients. Noncoding RNAs (ncRNAs) are implicated important in regulating gene expression. Thus, ncRNAs, especially microRNAs and long noncoding RNAs (lncRNAs), have gained widespread attention as crucial players in numerous physiological and pathological processes, including skeletal muscle atrophy. In this review, we comprehensively described the potential of circulating microRNAs as biomarkers, summarized the profiling of microRNAs and lncRNAs in atrophying muscles, as well as discussed the effects and underlying mechanisms of microRNA machinery proteins, microRNAs, and lncRNAs in skeletal muscle atrophy. Considering the large quantity and variety of ncRNAs, the understanding of ncRNAs in muscle atrophy is still very limited. Future studies are needed to elucidate the possibility of ncRNAs as diagnosis biomarkers and therapeutic targets in muscle atrophy.
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MicroARNs/genética , Atrofia Muscular/genética , ARN Largo no Codificante/genética , ARN no Traducido/genética , Expresión Génica , HumanosRESUMEN
The adult heart retains a limited ability to regenerate in response to injury. Although exercise can reduce cardiac ischaemia/reperfusion (I/R) injury, the relative contribution of cardiac cell proliferation including newly formed cardiomyocytes remains unclear. A 4-week swimming murine model was utilized to induce cardiac physiological growth. Simultaneously, the antineoplastic agent 5-fluorouracil (5-FU), which acts during the S phase of the cell cycle, was given to mice via intraperitoneal injections. Using EdU and Ki-67 immunolabelling, we showed that exercise-induced cardiac cell proliferation was blunted by 5-FU. In addition, the growth of heart in size and weight upon exercise was unaltered, probably due to the fact that exercise-induced cardiomyocyte hypertrophy was not influenced by 5-FU as demonstrated by wheat germ agglutinin staining. Meanwhile, the markers for pathological hypertrophy, including ANP and BNP, were not changed by either exercise or 5-FU, indicating that physiological growth still developed in the presence of 5-FU. Furthermore, we showed that CITED4, a key regulator for cardiomyocyte proliferation, was blocked by 5-FU. Meanwhile, C/EBPß, a transcription factor responsible for both cellular proliferation and hypertrophy, was not altered by treatment with 5-FU. Importantly, the effects of exercise in reducing cardiac I/R injury could be abolished when cardiac cell proliferation was attenuated in mice treated with 5-FU. In conclusion, cardiac cell proliferation is not necessary for exercise-induced cardiac physiological growth, but it is required for exercise-associated protection against I/R injury.
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Fluorouracilo/farmacología , Daño por Reperfusión Miocárdica/terapia , Miocitos Cardíacos/efectos de los fármacos , Condicionamiento Físico Animal , Fase S/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Fase S/genética , Transducción de Señal , Natación , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND/AIMS: Identification of novel biomarkers to identify acute heart failure (AHF) patients at high risk of mortality is an area of unmet clinical need. Recently, we reported that the baseline level of circulating miR-30d was associated with left ventricular remodeling in response to cardiac resynchronization therapy in advanced chronic heart failure patients. However, the role of circulating miR-30d as a prognostic marker of survival in patients with AHF has not been explored. METHODS: Patients clinically diagnosed with AHF were enrolled and followed up for 1 year. Quantitative reverse transcription polymerase chain reactions were used to determine serum miR-30d levels. The univariate logistic regression analysis and multivariate logistic regression analysis were used to determine the predictors for all-cause mortality in AHF patients. Kaplan-Meier survival analysis was used to analyze the role of miR-30d in prediction of survival. RESULTS: A total of 96 AHF patients were enrolled and followed up for 1 year. Serum miR-30d was significantly lower in AHF patients who expired in the one year follow-up period compared to those who survived. Univariate logistic regression analysis yielded 18 variables that were associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 4 variables including heart rate, hemoglobin, serum sodium, and serum miR-30d level associated with mortality. ROC curve analysis showed that hemoglobin, heart rate and serum sodium displayed poor prognostic value for AHF (AUCs not higher than 0.700) compared to miR-30d level (AUC = 0.806). Kaplan-Meier survival analysis confirmed that patients with higher serum miR-30d levels had significantly lower mortality (P=0.001). CONCLUSION: In conclusion, this study shows evidence for the predictive value of circulating miR-30d as 1-year all-cause mortality in AHF patients. Large multicentre studies are further needed to validate our findings and accelerate the transition to clinical utilization.
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Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico , MicroARNs/sangre , Remodelación Ventricular , Enfermedad Aguda , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Femenino , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca , Hemoglobinas/metabolismo , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Curva ROC , Sodio/sangreRESUMEN
Qiliqiangxin (QLQX), a traditional Chinese herbs medication, exerted protective effect in chronic heart failure patients in a multicenter randomized double-blind study. QLQX has also been found to improve cardiac function and reduce cardiac fibrosis in spontaneously hypertension animal model. However, the effect of longterm treatment with QLQX in such a condition and the related molecular mechanisms remain largely unknown. In the present study, thirteen-week-old spontaneously hypertensive rats (SHRs) were treated by daily intragastric administration of QLQX or saline for one year. Echocardiography, electron microscopy, and Masson's trichrome staining were used to determine cardiac function, mitochondria ultrastructure, and cardiac fibrosis, respectively. Quantitative reverse transcription polymerase chain reactions (qRT-PCRs) and Western blotting were used to determine gene expressions. We found that QLQX significantly improved cardiac function and reduced gene markers of pathological hypertrophy including ANP, BNP, and Myh7. QLQX also attenuated cardiac fibrosis and apoptosis in SHRs as evidenced by downregulation of α-SMA, collagen I, collagen III, and TGF-ß expressions and reduction of Bax to Bcl-2 ratio. Moreover, the damage of mitochondrial ultrastructure was greatly improved and the reduction of PPAR-α, PPAR-γ, and PGC-1α expression levels was significantly restored in SHRs by treatment with QLQX. In conclusion, longterm treatment with QLQX protects against cardiac remodeling and dysfunction in hypertension by increasing PPARs and PGC-1α.
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Medicamentos Herbarios Chinos/administración & dosificación , Hipertensión/tratamiento farmacológico , Medicina Tradicional China , Infarto del Miocardio/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Humanos , Hipertensión/fisiopatología , Hipertrofia/diagnóstico por imagen , Hipertrofia/tratamiento farmacológico , Hipertrofia/genética , Hipertrofia/patología , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/fisiopatología , Ratas , Ratas Endogámicas SHR , Remodelación VentricularRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and lifestyle, while exercise is beneficial for NAFLD. Dysregulated microRNAs (miRs) control the pathogenesis of NAFLD. However, whether exercise could prevent NAFLD via targeting microRNA is unknown. In this study, normal or high-fat diet (HF) mice were either subjected to a 16-week running program or kept sedentary. Exercise attenuated liver steatosis in HF mice. MicroRNA array and qRT-PCR demonstrated that miR-212 was overexpressed in HF liver, while reduced by exercise. Next, we investigated the role of miR-212 in lipogenesis using HepG2 cells with/without long-chain fatty acid treatment (± FFA). FFA increased miR-212 in HepG2 cells. Moreover, miR-212 promoted lipogenesis in HepG2 cells (± FFA). Fibroblast growth factor (FGF)-21, a key regulator for lipid metabolism, was negatively regulated by miR-212 at protein level in HepG2 cells. Meanwhile, FFA downregulated FGF-21 both at mRNA and protein levels in HepG2 cells. Also, FGF-21 protein level was reduced in HF liver, while reversed by exercise in vivo. Furthermore, siRNA-FGF-21 abolished the lipogenesis-reducing effect of miR-212 inhibitor in HepG2 cells (± FFA), validating FGF-21 as a target gene of miR-212. These data link the benefit of exercise and miR-212 downregulation in preventing NAFLD via targeting FGF-21.
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Regulación hacia Abajo/genética , Factores de Crecimiento de Fibroblastos/genética , MicroARNs/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Condicionamiento Físico Animal/fisiología , Animales , Línea Celular Tumoral , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Células Hep G2 , Humanos , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , ARN Mensajero/genéticaRESUMEN
Cardiac fibrosis is a fundamental constituent of a variety of cardiac dysfunction, making it a leading cause of death worldwide. However, no effective treatment for cardiac fibrosis is available. Therefore, novel therapeutics for cardiac fibrosis are highly needed. Recently, miR-19b has been found to be able to protect hydrogen peroxide (H2 O2 )-induced apoptosis and improve cell survival in H9C2 cardiomyocytes, while down-regulation of miR-19b had opposite effects, indicating that increasing miR-19b may be a new therapeutic strategy for attenuating cellular apoptosis during myocardial ischaemia-reperfusion injury. However, considering the fact that microRNAs might exert a cell-specific role, it is highly interesting to determine the role of miR-19b in cardiac fibroblasts. Here, we found that miR-19b was able to promote cardiac fibroblast proliferation and migration. However, miR-19b mimics and inhibitors did not modulate the expression level of collagen I. Pten was identified as a target gene of miR-19b, which was responsible for the effect of miR-19b in controlling cardiac fibroblast proliferation and migration. Our data suggest that the role of miR-19b is cell specific, and systemic miR-19b targeting in cardiac remodelling might be problematic. Therefore, it is highly needed and also urgent to investigate the role of miR-19b in cardiac remodelling in vivo.
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Movimiento Celular , Fibroblastos/citología , Fibroblastos/metabolismo , MicroARNs/metabolismo , Miocardio/citología , Animales , Animales Recién Nacidos , Movimiento Celular/genética , Proliferación Celular , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Ratas Sprague-DawleyRESUMEN
BACKGROUND/AIMS: Qiliqiangxin (QL), a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so) whether it is through modulation of specific hypertrophy-related microRNA. METHODS: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h) to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h). The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and ß-myosin heavy chain (MYH7) were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI) mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. RESULTS: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. CONCLUSION: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL on cardiomyocytes.
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Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , MicroARNs/metabolismo , Actinina/metabolismo , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Oligonucleótidos Antisentido/metabolismo , Fenilefrina/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Telocytes (TCs) are a distinct type of interstitial cells, which are featured with a small cellular body and long and thin elongations called telopodes (Tps). TCs have been widely identified in lots of tissues and organs including heart. Double staining for CD34/PDGFR-ß (Platelet-derived growth factor receptor ß) or CD34/Vimentin is considered to be critical for TC phenotyping. It has recently been proposed that CD34/PDGFR-α (Platelet-derived growth factor receptor α) is actually a specific marker for TCs including cardiac TCs although the direct evidence is still lacking. Here, we showed that cardiac TCs were double positive for CD34/PDGFR-α in primary culture. CD34/PDGFR-α positive cells (putative cardiac TCs) also existed in mice ventricle and human cardiac valves including mitral valve, tricuspid valve and aortic valve. Over 87% of cells in a TC-enriched culture of rat cardiac interstitial cells were positive for PDGFR-α, while CD34/PDGFR-α double positive cells accounted for 30.25% of the whole cell population. We show that cardiac TCs are double positive for CD34/PDGFR-α. Better understanding of the immunocytochemical phenotypes of cardiac TCs might help using cardiac TCs as a novel source in cardiac repair.
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Antígenos CD34/metabolismo , Miocardio/citología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Telocitos/metabolismo , Animales , Citometría de Flujo , Fluorescencia , Válvulas Cardíacas/citología , Humanos , Masculino , Ratones Endogámicos C57BL , Ratas Wistar , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Células del Estroma/metabolismoRESUMEN
Cardiac aging is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular and functional changes associated with cardiac aging and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of aging, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of aging on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac aging and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological aging. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of aging populations worldwide.
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Among its many cardiovascular benefits, exercise training improves heart function and protects the heart against age-related decline, pathological stress, and injury. Here, we focus on cardiac benefits with an emphasis on more recent updates to our understanding. While the cardiomyocyte continues to play a central role as both a target and effector of exercise's benefits, there is a growing recognition of the important roles of other, noncardiomyocyte lineages and pathways, including some that lie outside the heart itself. We review what is known about mediators of exercise's benefits-both those intrinsic to the heart (at the level of cardiomyocytes, fibroblasts, or vascular cells) and those that are systemic (including metabolism, inflammation, the microbiome, and aging)-highlighting what is known about the molecular mechanisms responsible.
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Exercise is a vital component in maintaining optimal health and serves as a prospective therapeutic intervention for various diseases. The human microbiome, comprised of trillions of microorganisms, plays a crucial role in overall health. Given the advancements in microbiome research, substantial databases have been created to decipher the functionality and mechanisms of the microbiome in health and disease contexts. This review presents an initial overview of microbiomics development and related databases, followed by an in-depth description of the multi-omics technologies for microbiome. It subsequently synthesizes the research pertaining to exercise-induced modifications of the microbiome and diseases that impact the microbiome. Finally, it highlights the potential therapeutic implications of an exercise-modulated microbiome in intestinal disease, obesity and diabetes, cardiovascular disease, and immune/inflammation-related diseases.
RESUMEN
Circulating circular RNAs (circRNAs) are emerging as novel biomarkers for cardiovascular diseases (CVDs). Machine learning can provide optimal predictions on the diagnosis of diseases. Here we performed a proof-of-concept study to determine if combining circRNAs with an artificial intelligence approach works in diagnosing CVD. We used acute myocardial infarction (AMI) as a model setup to prove the claim. We determined the expression level of five hypoxia-induced circRNAs, including cZNF292, cAFF1, cDENND4C, cTHSD1, and cSRSF4, in the whole blood of coronary angiography positive AMI and negative non-AMI patients. Based on feature selection by using lasso with 10-fold cross validation, prediction model by logistic regression, and ROC curve analysis, we found that cZNF292 combined with clinical information (CM), including age, gender, body mass index, heart rate, and diastolic blood pressure, can predict AMI effectively. In a validation cohort, CM + cZNF292 can separate AMI and non-AMI patients, unstable angina and AMI patients, acute coronary syndromes (ACS), and non-ACS patients. RNA stability study demonstrated that cZNF292 was stable. Knockdown of cZNF292 in endothelial cells or cardiomyocytes showed anti-apoptosis effects in oxygen glucose deprivation/reoxygenation. Thus, we identify circulating cZNF292 as a potential biomarker for AMI and construct a prediction model "CM + cZNF292."