RESUMO
Atherosclerosis is the major cause of coronary artery disease (CAD) which includes unstable angina, myocardial infarction, and heart failure. The onset of atherogenesis, a process of atherosclerotic lesion formation in the intima of arteries, is driven by lipid accumulation, a vicious cycle of reactive oxygen species (ROS)-induced oxidative stress and inflammatory reactions leading to endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) activation, and foam cell formation which further fuel plaque formation and destabilization. In recent years, there is a surge in the number of publications reporting the involvement of circular RNAs (circRNAs) in the pathogenesis of cardiovascular diseases, cancers, and metabolic syndromes. These studies have advanced our understanding on the biological functions of circRNAs. One of the most common mechanism of action of circRNAs reported is the sponging of microRNAs (miRNAs) by binding to the miRNAs response element (MRE), thereby indirectly increases the transcription of their target messenger RNAs (mRNAs). Individual networks of circRNA-miRNA-mRNA associated with atherogenesis have been extensively reported, however, there is a need to connect these findings for a complete overview. This review aims to provide an update on atherogenesis-related circRNAs and analyze the circRNA-miRNA-mRNA interactions in atherogenesis. The atherogenic mechanisms and clinical relevance of each atherogenesis-related circRNA were systematically discussed for better understanding of the knowledge gap in this area.
Assuntos
Aterosclerose , MicroRNAs , Humanos , RNA Circular/genética , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Aterosclerose/genética , Redes Reguladoras de GenesRESUMO
Accumulation of senescent endothelial cells can cause endothelium dysfunction which eventually leads to age-related vascular disorders. The senescent-associated secretory phenotype (SASP) cells secrete a plethora of soluble factors that negatively influence the surrounding tissue microenvironment. The present study sought to investigate the effects of exosomes, which are nano-sized extracellular vesicles known for intercellular communications secreted by SASP cells on young endothelial cells. Exosomes were isolated from the condition media of senescent human umbilical vein endothelial cells (HUVECs) and then confirmed by the detection of exosome specific CD63 and CD9 expressions, electron microscopy and acetylcholinesterase assay. The purified exosomes were used to treat young HUVECs. Exposure to exosomes repressed the expression of adherens junction proteins including vascular endothelial (VE)-cadherin and beta-catenin, decreased cell growth kinetics and impaired endothelial migration potential of young endothelial cells. These findings suggest that senescent HUVECs-secreted exosomes could disrupt barrier integrity that underpins endothelial barrier dysfunction in healthy young endothelial cells.
RESUMO
Circulating microRNAs (miRNAs) hold great potential as novel diagnostic markers for acute coronary syndrome (ACS). This study sought to identify plasma miRNAs that are differentially expressed in young ACS patients (mean age of 38.5 ± 4.3 years) and evaluate their diagnostic potentials. Small RNA sequencing (sRNA-seq) was used to profile plasma miRNAs. Discriminatory power of the miRNAs was determined using receiver operating characteristic (ROC) analysis. Thirteen up-regulated and 16 down-regulated miRNAs were identified in young ACS patients. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) validation showed miR-183-5p was significantly up-regulated (8-fold) in ACS patients with non-ST-segment elevated myocardial infarction (NSTEMI) whereas miR-134-5p, miR-15a-5p, and let-7i-5p were significantly down-regulated (5-fold, 7-fold and 3.5-fold, respectively) in patients with ST-segment elevated myocardial infarction (STEMI), compared to the healthy controls. MiR-183-5p had a high discriminatory power to differentiate NSTEMI patients from healthy controls (area under the curve (AUC) of ROC = 0.917). The discriminatory power for STEMI patients was highest with let-7i-5p (AUC = 0.833) followed by miR-134-5p and miR-15a-5p and this further improved (AUC = 0.935) with the three miRNAs combination. Plasma miR-183-5p, miR-134-5p, miR-15a-5p and let-7i-5p are deregulated in STEMI and NSTEMI and could be potentially used to discriminate the two ACS forms.
Assuntos
Síndrome Coronariana Aguda/sangue , MicroRNAs/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Síndrome Coronariana Aguda/patologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio sem Supradesnível do Segmento ST/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/patologiaRESUMO
miRNAs are important regulators of cellular senescence yet the extent of their involvement remains to be investigated. We sought to identify miRNAs that are involved in cytokine-induced premature senescence (CIPS) in endothelial cells. CIPS was established in young human pulmonary microvascular endothelial cells (HMVEC-Ls) following treatment with a sublethal dose (20ng/ml) of tumor necrosis factor alpha (TNF-α) for 15days. In parallel, HMVEC-Ls were grown and routinely passaged until the onset of replicative senescence (RS). Differential expression analysis following miRNA microarray profiling revealed an overlapped of eight deregulated miRNAs in both the miRNA profiles of RS and TNF-α-induced premature senescence cells. Amongst the deregulated miRNAs were members of the miR 17-92 cluster which are known regulators of angiogenesis. The role of hsa-miR-20b in TNF-α-induced premature senescence, a paralog member of the miR 17-92 cluster, was further investigated. Biotin-labeled hsa-miR-20b captured the enriched transcripts of retinoblastoma-like 1 (RBL1), indicating that RBL1 is a target of hsa-miR-20b. Knockdown of hsa-miR-20b attenuated premature senescence in the TNF-α-treated HMVEC-Ls as evidenced by increased cell proliferation, increased RBL1 mRNA expression level but decreased protein expression of p16INK4a, a cellular senescence marker. These findings provide an early insight into the role of hsa-miR-20b in endothelial senescence.
Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Pulmão/irrigação sanguínea , MicroRNAs/metabolismo , Microvasos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/genética , Microvasos/metabolismo , Microvasos/patologia , Interferência de RNA , Proteína p107 Retinoblastoma-Like/genética , Proteína p107 Retinoblastoma-Like/metabolismo , Fatores de Tempo , TransfecçãoRESUMO
Quassinoids are a group of diterpenoids found in plants from the Simaroubaceae family. They are also the major bioactive compounds found in Eurycoma longifolia which is commonly used as traditional medicine in South East Asia to treat various ailments including sexual dysfunction and infertility. These uses are attributed to its ability to improve testosterone level in men. Chronic consumption of E. longifolia extracts has been reported to increase testosterone level in men and animal model but its effect on prostate growth remains unknown. Therefore, the present study investigates the effects of a standardized total quassinoids composition (SQ40) containing 40% of the total quassinoids found in E. longifolia on LNCaP human prostate cancer cell line. SQ40 inhibited LNCaP cell growth at IC50 value of 5.97 µg/mL while the IC50 on RWPE-1 human prostate normal cells was 59.26 µg/mL. SQ40 also inhibited 5α-dihydrotestosterone-stimulated growth in LNCaP cells dose-dependently. The inhibitory effect of SQ40 in anchorage-independent growth of LNCaP cells was also demonstrated using soft agar assay. SQ40 suppressed LNCaP cell growth via G0/G1 phase arrest which was accompanied by the down-regulation of CDK4, CDK2, Cyclin D1 and Cyclin D3 and up-regulation of p21Waf1/Cip1 protein levels. SQ40 at higher concentrations or longer treatment duration can cause G2M growth arrest leading to apoptotic cell death as demonstrated by the detection of poly(ADP-ribose) polymerase cleavage in LNCaP cells. Moreover, SQ40 also inhibited androgen receptor translocation to nucleus which is important for the transactivation of its target gene, prostate-specific antigen (PSA) and resulted in a significant reduction of PSA secretion after the treatment. In addition, intraperitoneal injection of 5 and 10 mg/kg of SQ40 also significantly suppressed the LNCaP tumor growth on mouse xenograft model. Results from the present study suggest that the standardized total quassinoids composition from E. longifolia promotes anti-prostate cancer activities in LNCaP human prostate cancer cells.