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Homologous recombination (HR) is a major DNA double-strand break (DSB) repair pathway of clinical interest because of treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). Cooperation between RAD51 and BRCA2 is pivotal for DNA DSB repair, and its dysfunction induces HR deficiency and sensitizes cancer cells to PARPi. The depletion of the DEAD-box protein DDX11 was found to suppress HR in hepatocellular carcinoma (HCC) cells. The HR ability of HCC cells is not always dependent on the DDX11 level because of natural DDX11 mutations. In Huh7 cells, natural DDX11 mutations were detected, increasing the susceptibility of Huh7 cells to olaparib in vitro and in vivo. The HR deficiency of Huh7 cells was restored when CRISPR/Cas9-mediated knock-in genomic editing was used to revert the DDX11 Q238H mutation to wild type. The DDX11 Q238H mutation impeded the phosphorylation of DDX11 by ATM at serine 237, preventing the recruitment of RAD51 to damaged DNA sites by disrupting the interaction between RAD51 and BRCA2. Clinically, a high level of DDX11 correlated with advanced clinical characteristics and a poor prognosis and served as an independent risk factor for overall and disease-free survival in patients with HCC. We propose that HCC with a high level of wild-type DDX11 tends to be more resistant to PARPi because of enhanced recombination repair, and the key mutation of DDX11 (Q238H) is potentially exploitable.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Antineoplásicos/farmacología , Recombinación Homóloga/genética , ADN , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , ADN Helicasas/genética , ARN Helicasas DEAD-box/genética , Proteína BRCA2/genéticaRESUMEN
Extracellular vesicles (EVs), as part of the cellular secretome, have emerged as essential cell-cell communication regulators in multiple physiological and pathological processes. Previous studies have widely reported that mesenchymal stromal cell-derived EVs (MSC-EVs) have potential therapeutic applications in ischemic diseases or regenerative medicine by accelerating angiogenesis. MSC-EVs also exert beneficial effects on other vasculopathies, including atherosclerosis, aneurysm, vascular restenosis, vascular calcification, vascular leakage, pulmonary hypertension, and diabetic retinopathy. Consequently, the potential of MSC-EVs in regulating vascular homeostasis is attracting increasing interest. In addition to native or naked MSC-EVs, modified MSC-EVs and appropriate biomaterials for delivering MSC-EVs can be introduced to this area to further promote their therapeutic applications. Herein, we outline the functional roles of MSC-EVs in different vasculopathies and angiogenesis to elucidate how MSC-EVs contribute to maintaining vascular system homeostasis. We also discuss the current strategies to optimize their therapeutic effects, which depend on the superior bioactivity, high yield, efficient delivery, and controlled release of MSC-EVs to the desired regions, as well as the challenges that need to be overcome to allow their broad clinical translation.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Enfermedades Vasculares , Humanos , Isquemia , Fenómenos Fisiológicos CardiovascularesRESUMEN
The fat mass and obesity-associated (FTO) gene was the first obesity-susceptibility gene identified through a genome-wide association study (GWAS). A growing number of studies have suggested that genetic variants of FTO are strongly associated with the risk of cardiovascular diseases, including hypertension and acute coronary syndrome. In addition, FTO was also the first N6-methyladenosine (m6A) demethylase, suggesting the reversible nature of m6A modification. m6A is dynamically deposited, removed, and recognized by m6A methylases, demethylases, and m6A binding proteins, respectively. By catalyzing m6A demethylation on mRNA, FTO may participate in various biological processes by modulating RNA function. Recent studies demonstrated that FTO plays a pivotal role in the initiation and progression of cardiovascular diseases such as myocardial fibrosis, heart failure, and atherosclerosis and may hold promise as a potential therapeutic target for treating or preventing a variety of cardiovascular diseases. Here, we review the association between FTO genetic variants and cardiovascular disease risk, summarize the role of FTO as an m6A demethylase in cardiovascular disorders, and discuss future research directions and possible clinical implications.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/genética , Estudio de Asociación del Genoma Completo , ARN/metabolismo , ARN Mensajero/genética , Obesidad/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genéticaRESUMEN
Circular RNAs (circRNAs), characterized as single-stranded closed circular RNA molecules, have been established to exert pivotal functions in various biological or pathological processes. Nonetheless, the effects and underlying mechanisms concerning circRNAs on the aging and aging-related diseases remain elusive. We herein compared the expression patterns of circRNAs in young and senescent mouse embryonic fibroblasts (MEFs), and uncovered that circRNF169 was dramatically up-regulated in senescent MEFs compared with that in young MEFs. Therefore, we further digged into the role and potential mechanisms of circRNF169 in the senescence of MEFs. The results of senescence-associate-ß-galactosidase staining and BrdU incorporation assay showed that silencing of circRNF169 significantly delayed MEFs senescence and promoted cell proliferation, while ectopic expression of circRNF169 exhibited the opposite effects. Moreover, the dual-luciferase reporter assay confirmed that circRNF169 acted as an endogenous miR-30c-5p sponge, which accelerated cellular senescence by sequestering and inhibiting miR-30c-5p activity. Taken together, our results suggested that circRNF169 exerted a crucial role in cellular senescence through sponging miR-30c-5p and represented a promising target for aging intervention.
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Senescencia Celular , MicroARNs , ARN Circular , Animales , Proliferación Celular/genética , Senescencia Celular/genética , Fibroblastos/metabolismo , Ratones , MicroARNs/genética , MicroARNs/fisiología , ARN Circular/genética , ARN Circular/fisiologíaRESUMEN
Circular RNAs (circRNAs) have been established to be involved in numerous processes in the human genome, but their function in vascular aging remains largely unknown. In this study, we aimed to characterize and analyze the function of a circular intronic RNA, ciPVT1, in endothelial cell senescence. We observed significant downregulation of ciPVT1 in senescent endothelial cells. In proliferating endothelial cells, ciPVT1 knockdown induced a premature senescence-like phenotype, inhibited proliferation, and led to an impairment in angiogenesis. An in vivo angiogenic plug assay revealed that ciPVT1 silencing significantly inhibited endothelial tube formation and decreased hemoglobin content. Conversely, overexpression of ciPVT1 in old endothelial cells delayed senescence, promoted proliferation, and increased angiogenic activity. Mechanistic studies revealed that ciPVT1 can sponge miR-24-3p to upregulate the expression of CDK4, resulting in enhanced Rb phosphorylation. Moreover, enforced expression of ciPVT1 reversed the senescence induction effect of miR-24-3p in endothelial cells. In summary, the present study reveals a pivotal role for ciPVT1 in regulating endothelial cell senescence and may have important implications in the search of strategies to counteract the development of age-associated vascular pathologies.
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Senescencia Celular/genética , Quinasa 4 Dependiente de la Ciclina/genética , Células Endoteliales/metabolismo , MicroARNs/genética , ARN Circular/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , TransfecciónRESUMEN
Endothelial cell senescence is one of the most important causes of vascular dysfunction and atherosclerosis. Circular RNAs (circRNAs) are endogenous RNA molecules with covalently closed-loop structures, which have been reported to be abnormally expressed in many human diseases. However, the potential role of circRNAs in endothelial cell senescence and atherosclerosis remains largely unknown. Here, we compared the expression patterns of circRNAs in young and senescent human endothelial cells with RNA sequencing. Among the differentially expressed circRNAs, circGNAQ, a circRNA enriched in vascular endothelium, was significantly downregulated in senescent endothelial cells. circGNAQ silencing triggered endothelial cell senescence, as determined by a rise in senescence-associated ß-galactosidase activity, reduced cell proliferation, and suppressed angiogenesis; circGNAQ overexpression showed the opposite effects. Mechanistic studies revealed that circGNAQ acted as an endogenous miR-146a-5p sponge to increase the expression of its target gene PLK2 by decoying the miR-146a-5p, thereby delaying endothelial cell senescence. In vivo studies showed that circGNAQ overexpression in the endothelium inhibited endothelial cell senescence and atherosclerosis progression. These results suggest that circGNAQ plays critical roles in endothelial cell senescence and consequently the pathogenesis of atherosclerosis, implying that the management of circGNAQ provides a potential therapeutic approach for limiting the progression of atherosclerosis.
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Circular RNAs (circRNAs) represent a novel class of widespread and diverse endogenous RNA molecules. This unusual class of RNA species is generated by a back-splicing event of exons or introns, resulting in a covalently closed circRNA molecule. Accumulating evidence indicates that circRNA plays an important role in the biological functions of a network of competing endogenous RNA (ceRNA). CircRNAs can competitively bind to miRNAs and abolish the suppressive effect of miRNAs on target RNAs, thus regulating gene expression at the posttranscriptional level. The role of circRNAs as ceRNAs in the pathogenesis of cardiovascular and cerebrovascular diseases (CVDs) has been recently reported and highlighted. Understanding the underlying molecular mechanism could aid the discovery of therapeutic targets or strategies against CVDs. Here, we review the progress in studying the role of circRNAs as ceRNAs in CVDs, with emphasis on the molecular mechanism, and discuss future directions and possible clinical implications.
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Circular RNAs (circRNAs), a novel type of endogenous RNAs with covalently closed-loop structures, have become a new research hotspot in the RNA world. Their diversity, stability, evolutionary conservation, and cell type- or tissue-specific expression patterns endow circRNAs with various important biological functions. As a consequence, circRNAs are emerging as important regulators of physiological development and disease pathogenesis. Growing evidence has shown that circRNAs can regulate parental gene expression through diverse mechanisms, such as transcription and splicing regulation, microRNA (miRNA) sponges, mRNA traps, translational modulation, and post-translational modification. The study of circRNAs and how circRNAs regulate the expression of parental genes will facilitate a deeper understanding of their biological functions and provide new perspectives on their clinical application. Herein, we review the biogenesis of circRNAs, with a particular focus on the molecular mechanisms of circRNAs regulating their parental gene expression and the biological significance of such regulation.
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Aging is a complex biological process closely linked with the occurrence and development of age-related diseases. Despite recent advances in lifestyle management and drug therapy, the late diagnosis of these diseases causes severe complications, usually resulting in death and consequently impacting social economies. Therefore, the identification of reliable biomarkers and the creation of effective treatment alternatives for age-related diseases are needed. Circular RNAs (circRNAs) are a novel class of RNA molecules that form covalently closed loops capable of regulating gene expression at multiple levels. Several studies have reported the emerging functional roles of circRNAs in various conditions, providing new perspectives regarding cellular physiology and disease pathology. Notably, accumulating evidence demonstrates the involvement of circRNAs in the regulation of age-related pathologies, including cardio-cerebrovascular disease, neurodegenerative disease, cancer, diabetes, rheumatoid arthritis, and osteoporosis. Therefore, the association of circRNAs with these age-related pathologies highlights their potential as diagnostic biomarkers and therapeutic targets for better disease management. Here, we review the biogenesis and function of circRNAs, with a special focus on their regulatory roles in aging-related pathologies, as well as discuss their potential as biological biomarkers and therapeutic targets for these diseases.
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CircFOXO3 plays an important role in the pathogenesis of coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) at circRNA flanking introns may change its back-splicing and influence circRNA formation. Here, we aimed to investigate the influence of the polymorphisms at the circFOXO3 flanking introns on individual susceptibility to CAD. A total of 1185 individuals were included in the case-control study. In a multivariate logistic regression analysis, we determined that the rs12196996 G variant was significantly associated with increased CAD risk (OR = 1.36, P = 0.014). A similar trend of the association was observed in the recessive model (OR = 2.57, P = 0.003). Stratified analysis revealed a more significant association with CAD risk among younger subjects and non-smokers. Consistent with these results, the haplotype rs12196996G-rs9398171C containing rs12196996G allele was also associated with increased CAD risk (OR = 1.31, P = 0.013). Further investigation revealed that the rs12196996 GG genotype was associated with decreased circFOXO3 expression, but not linear FOXO3 levels. Taken together, our data provide the first evidence that the rs12196996 polymorphism at the circFOXO3 gene flanking intron is associated with CAD risk in the Chinese Han population, which is probably due to influence circFOXO3 levels.
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Enfermedad de la Arteria Coronaria , Proteína Forkhead Box O3/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , ARN Circular/genética , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Exosomes exist in almost all body fluid and contain diverse biological contents which may be reflective of disease state. Circular RNAs (circRNAs) are stable in structure and have a long half-life in exosomes without degradation, thus making them reliable biomarkers. However, the potential of exosomal circRNAs as biomarkers of coronary artery disease (CAD) remains to be established. Here, we aimed to investigate the expression levels and the potential use of exosomal circRNAs as diagnostic biomarkers for CAD. METHODS: CircRNA expression levels in exosomes obtained from three plasma samples of CAD patients and three paired controls were analyzed using RNA sequencing. Exosomal circRNAs obtained in the profiling phase were then verified in two-center validation cohorts. Finally, the ability of exosomal circRNAs, adjusting for Framingham Heart Study (FHS) risk factors, was determined to discriminate between CAD patients and non-CAD controls. RESULTS: 355 circRNAs were differentially expressed between these two groups: 164 were upregulated, and 191 were downregulated. Here, we selected the potential circRNAs (fold change > 4, P < 0.05) as candidate biomarkers for further validation. Our data showed that only hsa_circ_0005540 was significantly associated with CAD (P < 0.0001). After adjustment for risk factors, hsa_circ_0005540 showed a high discriminatory power for CAD in ROC analyses (AUC = 0.853; 95%confidence interval (CI) = 0.799 - 0.906, P < 0.001). CONCLUSION: Our results suggest that plasma exosomal hsa_circ_0005540 can be used as a promising diagnostic biomarker of CAD.
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Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Exosomas/genética , Perfilación de la Expresión Génica/métodos , ARN Circular/sangre , Adulto , Anciano , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/sangre , Diagnóstico Precoz , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN , Regulación hacia ArribaRESUMEN
The cytosolic isozyme of phosphoenolpyruvate carboxykinase (PCK1) was the first rate-limiting enzyme in the gluconeogenesis pathway, which exerted a critical role in maintaining the blood glucose levels. PCK1 has been established to be involved in various physiological and pathological processes, including glucose metabolism, lipid metabolism, diabetes, and tumorigenesis. Nonetheless, the association of PCK1 with aging process and the detailed underlying mechanisms of PCK1 on aging are still far to be elucidated. Hence, we herein constructed the PCK1-deficient (pck1Δ) and PCK1 overexpression (PCK1 OE) Saccharomyces cerevisiae. The results unveiled that PCK1 deficiency significantly shortened the replicative lifespan (RLS) in the S. cerevisiae, while overexpression of PCK1 prolonged the RLS. Additionally, we noted that the ROS level was significantly enhanced in PCK1-deficient strain and decreased in PCK1 OE strain. Then, a high throughput analysis by deep sequencing was performed in the pck1Δ and wild-type strains, in an attempt to shed light on the effect of PCK1 on the lifespan of aging process. The data showed that the most downregulated mRNAs were enriched in the regulatory pathways of glucose metabolism. Fascinatingly, among the differentially expressed mRNAs, PFK1 was one of the most upregulated genes, which was involved in the glycolysis process and ROS generation. Thus, we further constructed the pfk1Δpck1Δ strain by deletion of PFK1 in the PCK1-deficient strain. The results unraveled that pfk1Δpck1Δ strain significantly suppressed the ROS level and restored the RLS of pck1Δ strain. Taken together, our data suggested that PCK1 deficiency enhanced the ROS level and shortened the RLS of S. cerevisiae via PFK1.
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Regulación Enzimológica de la Expresión Génica , Regulación Fúngica de la Expresión Génica , Fosfoenolpiruvato Carboxiquinasa (ATP) , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Fosfoenolpiruvato Carboxiquinasa (ATP)/deficiencia , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
BACKGROUND: Atherosclerosis is the primary cause of coronary artery disease (CAD), and stearoyl-CoA desaturase (SCD) is associated with atherosclerosis. However, the associations between variants of SCD and CAD have not yet been decided. METHODS: This study analyzed SCD rs41290540 single-nucleotide polymorphism (SNP) in the 3'-untranslated region for an association with a risk of CAD among the Chinese Han population. CAD patients and controls were genotyped for SNP rs41290540 in SCD by SNaPshot. The binding affinity of miR-498 to rs41290540 was determined by a luciferase assay, and SCD expression was assessed using Western blot. RESULTS: A total of 969 CAD patients and 1,095 control subjects were involved in this study. The SCD rs41290540CC genotype is associated with a decreased risk of CAD compared with the AA genotype. Furthermore, the CC genotype is associated with lower serum total cholesterol (TC). Western blot analysis demonstrated that miR-498 suppressed the expression of SCD. A luciferase assay confirmed that rs41290540 A>C variation in the SCD 3'UTR inhibits miR-498 binding. CONCLUSION: This study demonstrates that the SCD rs41290540 may be associated with a decreased risk of CAD, lower serum TC, and decreased miR-498 binding.
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Enfermedad de la Arteria Coronaria/genética , Polimorfismo de Nucleótido Simple , Estearoil-CoA Desaturasa/genética , Anciano , Glucemia/metabolismo , Presión Sanguínea , Células Cultivadas , Enfermedad de la Arteria Coronaria/patología , Femenino , Células HEK293 , Humanos , Lípidos/sangre , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Estearoil-CoA Desaturasa/metabolismoRESUMEN
OBJECTIVES: Accumulating evidences have shown that polymorphisms in miRNA genes play an important role in the susceptibility to coronary artery disease (CAD). A potentially functional polymorphism rs4938723, which located within the promoter region of pri-miR-34b/c, may affect the expression of miR-34b/c. To date, the role of genetic variant in pri-miR-34b/c on CAD risk is still unknown. Here we aimed to evaluate the association of Pri-miR-34b/c rs4938723 polymorphism with individual susceptibility to CAD in a Chinese Han population. METHODS: Genotyping was performed in a case-control study of 563 patients and 646 controls using polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The association of rs4938723 with CAD risk was evaluated using logistic regression analysis with SPSS software. RESULTS: We found that the C allele of pri-miR-34b/c rs4938723 was significantly associated with a decreased risk of CAD when compared with the T allele (OR = 0.76, 95% CI = 0.62-0.95, p = 0.015). Consistently, compared with those carrying TT genotype, the CC homozygotes displayed significantly reduced risk for CAD (OR = 0.54, 95% CI = 0.32-0.91, p = 0.021). Similar trend of the reduced risk for CAD was detected when the CT and CC genotypes were combined (OR = 0.75, 95% CI = 0.57-0.99, p = 0.044). Stratified analysis of pri-miR-34b/c rs4938723 revealed a more significant association of C allele with decreased CAD risk among older subjects, male and non-smokers. CONCLUSIONS: Our findings suggest that the pri-miR-34b/c rs4938723 polymorphism is associated with CAD susceptibility in the Chinese Han population. Further studies are warranted to confirm the general validity of our findings.
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Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad/genética , MicroARNs/genética , Pueblo Asiatico , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
PURPOSE OF THE STUDY: Genome-wide association studies have revealed an association of ADAMTS7 polymorphisms with the risk of cardiovascular diseases. Nonetheless, the role of ADAMTS7 polymorphisms on myocardial infarction (MI) risk remains poorly understood. Here, we aim to evaluate the effect of ADAMTS7 tag single nucleotide polymorphisms (SNPs) on individual susceptibility to MI. STUDY DESIGN: Genotyping of the four tagSNPs (rs1994016, rs3825807, rs4380028 and rs7173743) was performed in 232 MI cases and 661 control subjects using PCR-ligase detection reaction (LDR) method. The association of these four tagSNPs with MI risk was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that ADAMTS7 tagSNP rs3825807 exhibited a significant effect on MI risk. Compared with the TT homozygotes, the CT genotype (OR1.93, 95% CI1.30to 2.85, Pc=0.004) and the combined CC/CT genotypes (OR1.70, 95% CI1.16 to 2.50, Pc=0.028) were statistically significantly associated with the increased risk for MI. Further stratified analysis revealed a more significant association with MI risk among older subjects, hypertensives, non-diabetics and patients with hyperlipidaemia. Consistently, the haplotype rs1994016T-rs3825807C containing rs3825807 C allele exhibited increased MI risk (OR1.52, 95% CI1.10 to 2.10, p=0.010). However, we did not detect any association of the other three tagSNPs with MI risk. CONCLUSIONS: Our finding suggest that ADAMTS7 tagSNP rs3825807 contributes to MI susceptibility in the Chinese Han population. Further studies are necessary to conï¬rm the general validity of our ï¬ndings and to clarify the underlying mechanism for this association.
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Proteína ADAMTS7/genética , Infarto del Miocardio/genética , Estudios de Casos y Controles , China/etnología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etnología , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Aging is a multifactorial process characterized by the progressive deterioration of physiological functions. Among the multiple molecular mechanisms, microRNAs (miRNAs) have increasingly been implicated in the regulation of Aging process. However, the contribution of miRNAs to physiological Aging and the underlying mechanisms remain elusive. We herein performed high-throughput analysis using miRNA and mRNA microarray in the physiological Aging mouse, attempted to deepen into the understanding of the effects of miRNAs on Aging process at the "network" level. The data showed that various p53 responsive miRNAs, including miR-124, miR-34a and miR-29a/b/c, were up-regulated in Aging mouse compared with that in Young mouse. Further investigation unraveled that similar as miR-34a and miR-29, miR-124 significantly promoted cellular senescence. As expected, mRNA microarray and gene co-expression network analysis unveiled that the most down-regulated mRNAs were enriched in the regulatory pathways of cell proliferation. Fascinatingly, among these down-regulated mRNAs, Ccna2 stood out as a common target of several p53 responsive miRNAs (miR-124 and miR-29), which functioned as the antagonist of p21 in cell cycle regulation. Silencing of Ccna2 remarkably triggered the cellular senescence, while Ccna2 overexpression delayed cellular senescence and significantly reversed the senescence-induction effect of miR-124 and miR-29. Moreover, these p53 responsive miRNAs were significantly up-regulated during the senescence process of p21-deficient cells; overexpression of p53 responsive miRNAs or knockdown of Ccna2 evidently accelerated the cellular senescence in the absence of p21. Taken together, our data suggested that the p53/miRNAs/Ccna2 pathway might serve as a novel senescence modulator independent of p53/p21 pathway.
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Senescencia Celular , Ciclina A2/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , MicroARNs/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Células Cultivadas , Senescencia Celular/genética , Ciclina A2/deficiencia , Ciclina A2/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Células 3T3 NIH , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Circular RNAs (circRNAs), a large novel type of endogenous transcripts, have become a new research hotspot in the field of RNA biology. CircRNAs are mainly generated from exons or introns via multiple mechanisms, and the majority of circRNAs are stable and conserved across different species. Recent studies have revealed that circRNAs can function as miRNA sponges, binding partners of proteins, regulators of transcription, or can even be translated into proteins. Growing evidence has demonstrated that circRNAs play important roles in a wide variety of biological processes such as cell proliferation, apoptosis and senescence, and may serve as potential diagnostic biomarkers or therapeutic targets for various cardiovascular diseases. Here, we review the biogenesis, properties and biological function of circRNAs, and summarize their roles in cardiovascular disorders.
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Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Empalme Alternativo , Apoptosis , Sitios de Unión , Biomarcadores/metabolismo , Proliferación Celular , Regulación de la Expresión Génica , Humanos , MicroARNs/metabolismo , Miocitos del Músculo Liso/fisiología , Unión Proteica , Biosíntesis de ProteínasRESUMEN
Endothelin-1 (ET-1) plays important roles in endothelial dysfunction, vascular physiology, inflammation, and atherosclerosis. Nonetheless, the role of ET-1 (EDN1) gene variants on coronary artery disease (CAD) risk remains poorly understood. The aim of the present study was to evaluate the role of EDN1 gene polymorphisms on individual susceptibility to CAD. We genotyped five tagSNPs (single-nucleotide polymorphisms) (rs6458155, rs4145451, rs9369217, rs3087459, and rs2070699) within EDN1 gene in 525 CAD patients and 675 control subjects. In a multivariate logistic regression analysis, we detected an association of rs6458155 in EDN1 gene with the CAD risk; compared with the TT homozygotes, the CT heterozygotes (odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.02-2.29, P=0.040) and the CC homozygotes (OR = 1.55, 95% CI = 1.01-2.36, P=0.043) were statistically significantly associated with the increased risk for CAD. A similar trend of the association was found in dominant model (OR = 1.53, 95% CI = 1.05-2.25, P=0.029). Consistently, the haplotype rs6458155C-rs4145451C containing rs6458155 C allele exhibited the increased CAD risk (OR = 1.22, 95% CI = 1.03-1.43, and P=0.018). In addition, CT genotype of rs6458155 conferred the increased plasma ET-1 levels compared with TT genotype (P<0.05). No association of the other four tagSNPs in EDN1 gene with CAD risk was observed. In conclusion, our study provides the first evidence that EDN1 tagSNP rs6458155 is associated with CAD risk in the Chinese Han population, which is probably due to the influence of the circulating ET-1 levels.
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Enfermedad de la Arteria Coronaria/genética , Endotelina-1/genética , Polimorfismo de Nucleótido Simple , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , Endotelina-1/sangre , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Accumulating evidences have shown that miRNAs are directly or indirectly involved in a variety of biological processes, and closely associated with diverse human diseases, including cardiovascular diseases. SNPs locating within pri/pre-miRNA can affect miRNA processing and binding ability of target genes. MiR-27a, miR-26a-1 miR-100, miR-126 and miR-218 were reported to be associated with pathogenesis of myocardial infarction (MI). Here we aimed to evaluate the potential association of five polymorphisms in these pri/pre-miRNAs with individual susceptibility to MI in a Chinese Han population. METHODS: Genotyping was performed in 287 MI cases and 646 control subjects using polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The association of these SNPs with MI risk was performed with SPSS software. RESULTS: In a logistic regression analysis, we found that AG heterozygote (OR = 0.40, 95% CI = 0.21-0.76, Pa = 0.005) or AA homozygote (OR = 0.40, 95% CI = 0.22-0.75, Pa = 0.004) of pre-miR-27a rs895819 had a reduced susceptibility to MI in comparison with GG homozygote. Similarly, a reduced risk of MI was detected when the AG and AA genotypes were combined (OR = 0.40, 95% CI = 0.22-0.74, Pa = 0.003). However, no significant association between pri-miR-26a-1 pri-miR-100, pri-miR-126 and pri-miR-218 polymorphisms and MI risk was observed under the allelic and established genetic models. Further stratified analysis of pre-miR-27a rs895819 revealed a more significant association of AG + AA genotypes with MI risk among younger, male and smoking subjects. Interestingly, AG and AA genotypes of the rs895819 polymorphism conferred about 0.17 mmol/L and 0.18 mmol/L increase in HDL-C levels compared to GG genotype. CONCLUSIONS: Our findings suggest that the pre-miR-27a rs895819 polymorphism is associated with MI susceptibility in the Chinese Han population, which probably due to influence the HDL-C levels.
Asunto(s)
Predisposición Genética a la Enfermedad , MicroARNs/genética , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple , Anciano , Alelos , Pueblo Asiatico , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica , Frecuencia de los Genes , Heterocigoto , Homocigoto , Humanos , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Infarto del Miocardio/etnología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Oportunidad Relativa , Factores de RiesgoRESUMEN
Cellular senescence is an irreversible growth arrest of cells that maintain their metabolic activities. Premature senescence can be induced by different stress factors and occurs in mouse embryonic fibroblasts (MEFs) derived from Zmpste24 metalloproteinasedeficient mice, a progeria mouse model of HutchinsonGilford Progeria Syndrome. Previous studies have shown that miR3425p, an intronic microRNA (miRNA/miR) reportedly involved in ageing associated diseases, is downregulated in Zmpste24/ MEFs. However, whether miR3425p is associated with the premature senescence phenotype of Zmpste24/ MEFs remains unclear. Thus, the present study investigated the effects of miR3425p on cellular senescence and cell proliferation in Zmpste24/ MEFs. The results showed that miR3425p overexpression ameliorated the cellular senescence phenotype to a certain extent, promoted cell proliferation and increased the G2+M cell cycle phase in Zmpste24/ MEFs. Nonetheless, it was difficult to observe the opposite cell phenotypes in wildtype (WT) MEFs transfected with the miR3425p inhibitor. Growtharrestspecific 2 (GAS2) was identified as a target gene of miR3425p in Zmpste24/ MEFs. In addition, miR3425p was identified to be downregulated in WT MEFs during replicative senescence, while Gas2 was upregulated. Taken together, these findings suggest that downregulated miR3425p is involved in regulating cell proliferation and cell cycles in Zmpste24/ MEFs by suppressing GAS2 in vitro.