RESUMO
BACKGROUND: Increasing evidence suggests that long noncoding RNAs play significant roles in vascular biology and disease development. One such long noncoding RNA, PSMB8-AS1, has been implicated in the development of tumors. Nevertheless, the precise role of PSMB8-AS1 in cardiovascular diseases, particularly atherosclerosis, has not been thoroughly elucidated. Thus, the primary aim of this investigation is to assess the influence of PSMB8-AS1 on vascular inflammation and the initiation of atherosclerosis. METHODS: We generated PSMB8-AS1 knockin and Apoe (Apolipoprotein E) knockout mice (Apoe-/-PSMB8-AS1KI) and global Apoe and proteasome subunit-ß type-9 (Psmb9) double knockout mice (Apoe-/-Psmb9-/-). To explore the roles of PSMB8-AS1 and Psmb9 in atherosclerosis, we fed the mice with a Western diet for 12 weeks. RESULTS: Long noncoding RNA PSMB8-AS1 is significantly elevated in human atherosclerotic plaques. Strikingly, Apoe-/-PSMB8-AS1KI mice exhibited increased atherosclerosis development, plaque vulnerability, and vascular inflammation compared with Apoe-/- mice. Moreover, the levels of VCAM1 (vascular adhesion molecule 1) and ICAM1 (intracellular adhesion molecule 1) were significantly upregulated in atherosclerotic lesions and serum of Apoe-/-PSMB8-AS1KI mice. Consistently, in vitro gain- and loss-of-function studies demonstrated that PSMB8-AS1 induced monocyte/macrophage adhesion to endothelial cells and increased VCAM1 and ICAM1 levels in a PSMB9-dependent manner. Mechanistic studies revealed that PSMB8-AS1 induced PSMB9 transcription by recruiting the transcription factor NONO (non-POU domain-containing octamer-binding protein) and binding to the PSMB9 promoter. PSMB9 (proteasome subunit-ß type-9) elevated VCAM1 and ICAM1 expression via the upregulation of ZEB1 (zinc finger E-box-binding homeobox 1). Psmb9 deficiency decreased atherosclerotic lesion size, plaque vulnerability, and vascular inflammation in Apoe-/- mice in vivo. Importantly, endothelial overexpression of PSMB8-AS1-increased atherosclerosis and vascular inflammation were attenuated by Psmb9 knockout. CONCLUSIONS: PSMB8-AS1 promotes vascular inflammation and atherosclerosis via the NONO/PSMB9/ZEB1 axis. Our findings support the development of new long noncoding RNA-based strategies to counteract atherosclerotic cardiovascular disease.
Assuntos
Aterosclerose , Placa Aterosclerótica , RNA Longo não Codificante , Animais , Humanos , Camundongos , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/patologia , Complexo de Endopeptidases do Proteassoma/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Atherosclerosis is a chronic inflammatory disease of arterial wall, and circulating monocyte adhesion to endothelial cells is a crucial step in the pathogenesis of atherosclerosis. Epithelial-stromal interaction 1 (EPSTI1) is a novel gene, which is dramatically induced by epithelial-stromal interaction in human breast cancer. EPSTI1 expression is not only restricted to the breast but also in other normal tissues. In this study we investigated the role of EPSTI1 in monocyte-endothelial cell adhesion and its expression pattern in atherosclerotic plaques. We showed that EPSTI1 was dramatically upregulated in human and mouse atherosclerotic plaques when compared with normal arteries. In addition, the expression of EPSTI1 in endothelial cells of human and mouse atherosclerotic plaques is significantly higher than that of the normal arteries. Furthermore, we demonstrated that EPSTI1 promoted human monocytic THP-1 cell adhesion to human umbilical vein endothelial cells (HUVECs) via upregulating VCAM-1 and ICAM-1 expression in HUVECs. Treatment with LPS (100, 500, 1000 ng/mL) induced EPSTI1 expression in HUVECs at both mRNA and protein levels in a dose- and time-dependent manner. Knockdown of EPSTI1 significantly inhibited LPS-induced monocyte-endothelial cell adhesion via downregulation of VCAM-1 and ICAM-1. Moreover, we revealed that LPS induced EPSTI1 expression through p65 nuclear translocation. Thus, we conclude that EPSTI1 promotes THP-1 cell adhesion to endothelial cells by upregulating VCAM-1 and ICAM-1 expression, implying its potential role in the development of atherosclerosis.
Assuntos
Aterosclerose , Placa Aterosclerótica , Animais , Humanos , Camundongos , Aterosclerose/metabolismo , Adesão Celular , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos , Monócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Placa Aterosclerótica/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
BACKGROUND: Stent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear. METHODS: The mouse common right carotid arteries were ligated for 16 or 30 days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments. RESULTS: Ferroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-L-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs. CONCLUSIONS: Ferroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.
Assuntos
Ferroptose , Neointima , Acetilcisteína/farmacologia , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Hiperplasia/metabolismo , Ferro/metabolismo , Ferro/farmacologia , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteopontina/metabolismo , Osteopontina/farmacologia , Fenótipo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Miosinas de Músculo Liso/metabolismoRESUMO
Long non-coding RNAs (lncRNAs) are emerging as important players in gene regulation and cardiovascular diseases. However, the roles of lncRNAs in atherosclerosis are poorly understood. In the present study, we found that the levels of NIPA1-SO were decreased while those of NIPA1 were increased in human atherosclerotic plaques. Furthermore, NIPA1-SO negatively regulated NIPA1 expression in human umbilical vein endothelial cells (HUVECs). Mechanistically, NIPA1-SO interacted with the transcription factor FUBP1 and the NIPA1 gene. The effect of NIPA1-SO on NIPA1 protein levels was reversed by the knockdown of FUBP1. NIPA1-SO overexpression increased, whilst NIPA1-SO knockdown decreased BMPR2 levels; these effects were enhanced by the knockdown of NIPA1. The overexpression of NIPA1-SO reduced while NIPA1-SO knockdown increased monocyte adhesion to HUVECs; these effects were diminished by the knockdown of BMPR2. The lentivirus-mediated-overexpression of NIPA1-SO or gene-targeted knockout of NIPA1 in low-density lipoprotein receptor-deficient mice reduced monocyte-endothelium adhesion and atherosclerotic lesion formation. Collectively, these findings revealed a novel anti-atherosclerotic role for the lncRNA NIPA1-SO and highlighted its inhibitory effects on vascular inflammation and intracellular cholesterol accumulation by binding to FUBP1 and consequently repressing NIPA1 expression.
Assuntos
Aterosclerose , Placa Aterosclerótica , RNA Longo não Codificante , Humanos , Animais , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Proteínas de Membrana/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/farmacologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/farmacologiaRESUMO
OBJECTIVE: To test the validity and reliability of the Chinese version of Mobile Phone Involvement Questionnaire (MPIQ) in college students. METHODS: We assessed the degree of phone dependence using the MPIQ among 2122 college students. One month later, 60 students were randomly selected for assessment with the MPIQ, and the ROC curve was generated to evaluate the true positive rate (sensitivity) and false positive rate at different cutoff values to determine the optimal cutoff score of the MPIQ. RESULTS: Among 98.9% of the participants who finished all the items, their MPIQ scores show a positive skew distribution and a one-factor structure. The load scores of the items ranged from 0.54 to 0.77. The Cronbach's α coefficient and the Spearman Brown split reliability were 0.84 and 0.83, respectively, the correlation coefficients between the items and total score ranged from 0.54 to 0.76, and the test-retest reliability was 0.48 (P < 0.001). At the optimal cut-off score of 32, the sensitivity and the specificity of the MPIQ were 0.634 and 0.652, respectively. CONCLUSIONS: At the optimal cut-off score of 32, the MPIQ has good validity and reliability for assessing phone dependence among college students.
Assuntos
Telefone Celular , Estudantes , Humanos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
The trichothiodystrophy group A protein (TTDA) functions in nucleotide excision repair and basal transcription. TTDA plays a role in cancers and serves as a prognostic and predictive factor in high-grade serous ovarian cancer; however, its role in human glioma remains unknown. Here, we found that TTDA was overexpressed in glioma tissues. In vitro experiments revealed that TTDA overexpression inhibited apoptosis of glioma cells and promoted cell growth, whereas knockdown of TTDA had the opposite effect. Increased TTDA expression significantly decreased the Bax/Bcl2 ratio and the level of cleaved-caspase3. TTDA interacted with the p53 gene at the -1959 bp and -1530 bp region and regulated its transcription, leading to inhibition of the p53-Bax/Bcl2 mitochondrial apoptosis pathway in glioma cells. These results indicate that TTDA is an upstream regulator of p53-mediated apoptosis and acts as an oncogene, suggesting its value as a potential molecular target for the diagnosis and treatment of glioma.
Assuntos
Apoptose/fisiologia , Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioma/patologia , Fatores de Transcrição/metabolismo , Proliferação de Células/fisiologia , Humanos , Oncogenes , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
OBJECTIVE: To investigate the association of mobile phone use with sleep disorder and unhealthy eating behavior among college students of a medical university in Guangzhou. METHODS: Mobile Phone Involvement Questionnaire (MPIQ), Pittsburgh Sleep Quality Index (PSQI) and the Three Factor Eating Questionnaire Revised 21 Item (TFEQ-R21) were used to survey 2122 undergraduates of the medical university. One-sample t test, One-way ANOVA and multiple linear regression analysis were used to analyze the data. RESULTS: Age, body mass index (BMI), phone use before sleep, phone use frequency, sleep quality (assessed by total PSQI score) and the dimension scores of TFEQ-R21 for uncontrolled eating, cognitive restraint, and emotional eating were all significantly correlated with the total score of MPIQ (P < 0.05). Phone use before sleep, high frequency of mobile phone use, poor sleep quality and emotional eating were associated with high MPIQ scores, while lower cognitive restraint and emotional eating tendency were correlated with lower scores of MPIQ. Bivariate analysis revealed that age (r=0.088, P < 0.001), BMI (r=0.055, P < 0.05), PSQI scores (r=0.204, P < 0.001), TFEQ-UE scores (r=0.199, P < 0.001), TFEQ-CR scores (r=-0.076, P < 0.001), TFEQ-EE scores (r=0.170, P < 0.001), phone use before sleep (r=0.429, P < 0.001), and phone use frequency (r=0.316, P < 0.001) were all significantly correlated with MPIQ scores; multiple linear regression analysis showed that model 4 incorporating the scores of TFEQ-UE, TFEQ-CR, and TFEQ-EE explained up to 21.8% of the main effect (adjusted R2= 21.5%). CONCLUSIONS: Mobile phone overuse is associated with poor sleep quality and unhealthy eating behaviors, and education and interventions for mobile phone use is essential among college students.