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1.
Arterioscler Thromb Vasc Biol ; 41(3): 1191-1204, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33406853

RESUMEN

OBJECTIVE: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na+/K+-ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na+/K+-ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. CONCLUSIONS: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.


Asunto(s)
Aterosclerosis/genética , ARN Largo no Codificante/genética , Animales , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Células Cultivadas , Colesterol/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Canales Iónicos/genética , Canales Iónicos/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Persona de Mediana Edad , Placa Aterosclerótica/etiología , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , ARN Largo no Codificante/metabolismo , Proteína EWS de Unión a ARN/antagonistas & inhibidores , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Regulación hacia Arriba
2.
Physiol Genomics ; 51(12): 644-656, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31682178

RESUMEN

Long noncoding (lnc)RNAs have been implicated in the development and progression of atherosclerosis. However, the expression and mechanism of action of lncRNAs in atherosclerosis are still unclear. We implemented microarray analysis in human advanced atherosclerotic plaques and normal arterial intimae to detect the lncRNA and mRNA expression profile. Gene Ontology functional enrichment and pathway analyses were applied to explore the potential functions and pathways involved in the pathogenesis of atherosclerosis. A total of 236 lncRNAs and 488 mRNAs were selected for further Ingenuity Pathway Analysis. Moreover, quantitative RT-PCR tests of most selected lncRNAs and mRNAs with high fold changes were consistent with the microarray data. We also performed ELISA to investigate the corresponding proteins levels of selected genes and showed that serum levels of SPP1, CD36, ATP6V0D2, CHI3L1, MYH11, and BDNF were differentially expressed in patients with coronary heart disease compared with healthy subjects. These proteins correlated with some biochemical parameters used in the diagnosis of cardiovascular diseases. Furthermore, receiver operating characteristic analysis showed a favorable diagnostic performance. The microarray profiling analysis and validation of differentially-expressed lncRNAs and mRNAs in atherosclerosis not only provide new insights into the pathogenesis of this disease but may also reveal new biomarkers for its diagnosis and treatment.


Asunto(s)
Aterosclerosis/sangre , Aterosclerosis/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , ARN Mensajero/sangre , ARN Mensajero/genética , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Voluntarios Sanos , Humanos , Masculino , Placa Aterosclerótica/química , Reacción en Cadena en Tiempo Real de la Polimerasa , Túnica Íntima/química
3.
J Cell Biochem ; 120(8): 13775-13782, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30938872

RESUMEN

Atherosclerosis is a complex inflammatory disease that involves disrupted cellular cholesterol levels and formation of foam cells. Studies about long noncoding RNA (lncRNA) have revealed its function in the development of atherosclerosis, by mediating reverse cholesterol transport and formation of foam cells. In this study, we found that oxidized low-density lipoprotein (ox-LDL) markedly decreased lncRNA AC096664.3 in vascular smooth muscle cells (VSMCs) and THP-1 macrophages. We also found that ox-LDL reduced ATP-binding cassette (ABC) G1 through inhibiting lncRNA AC096664.3 in VSMCs. Further experiments showed that the downregulation of lncRNA AC096664.3 reduced ABCG1 expression through inhibiting the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) and that ox-LDL reduced ABCG1 expression through inhibiting the expression of PPAR-γ. Furthermore, we discovered that ox-LDL inhibited ABCG1 via the lncRNA AC096664.3/PPAR-γ/ABCG1 pathway, which led to an increase in total and free cholesterol in VMSCs. Thus, we confirmed that ox-LDL induces cholesterol accumulation via the lncRNA AC096664.3/PPAR-γ/ABCG1 pathway in VSMCs, indicating a promising novel therapy in protecting against atherosclerosis.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Colesterol/metabolismo , Homeostasis , PPAR gamma/metabolismo , ARN Largo no Codificante/metabolismo , Transducción de Señal , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Colesterol/genética , Humanos , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , PPAR gamma/genética , ARN Largo no Codificante/genética , Células THP-1
4.
Mech Ageing Dev ; 211: 111803, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36963468

RESUMEN

Yippee-like 2 (YPEL2) is expressed in tissues and organs enriched in vascular networks, such as heart, kidney, and lung. However, the roles of YPEL2 in endothelial cell senescence and the expression of YPEL2 in atherosclerotic plaques have not yet been investigated. Here, we report the essential role of YPEL2 in promoting senescence in human umbilical vein endothelial cells (HUVECs) and the upregulation of YPEL2 in human atherosclerotic plaques. YPEL2 was significantly upregulated in both H2O2-induced senescent HUVECs and the arteries of aged mice. Endothelial YPEL2 deficiency significantly decreased H2O2-increased senescence-associated beta-galactosidase (SA-ß-gal) activity and reversed H2O2-inhibited cell viability. Additionally, endothelial YPEL2 knockdown reduced H2O2-promoted THP-1 cell adhesion to HUVECs and downregulated ICAM1 and VCAM1 expression. Mechanistic studies divulged that the p53/p21 pathway was involved in YPEL2-induced cellular senescence. We conclude that YPEL2 promotes cellular senescence via the p53/p21 pathway and that YPEL2 expression is elevated in atherosclerosis. These findings reveal YPEL2 as a potential therapeutic target in aging-associated diseases.


Asunto(s)
Senescencia Celular , Células Endoteliales , Placa Aterosclerótica , Animales , Humanos , Ratones , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Peróxido de Hidrógeno , Placa Aterosclerótica/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células Endoteliales/metabolismo
5.
J Adv Res ; 54: 29-42, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-36736696

RESUMEN

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.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , ARN Largo no Codificante , Humanos , Animales , Ratones , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/farmacología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/farmacología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/farmacología
6.
Atherosclerosis ; 312: 43-53, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32971395

RESUMEN

BACKGROUND AND AIMS: Long noncoding RNAs (lncRNAs) have recently been implicated in many biological and disease processes, but the exact mechanism of their involvement in atherosclerosis is unclear. The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic lesions. This study aimed to investigate the potential effects of lncRNA ZNF800, a previously uncharacterized lncRNA, on VSMC proliferation and migration. METHODS: The expression of lncRNA ZNF800 in atherosclerotic plaque tissues was detected using reverse transcription-quantitative PCR (RT-qPCR), while the role and mechanism of lncRNA ZNF800 in proliferation and migration of VSMCs were investigated by CCK8 assay, transwell assay, scratch wound assay, RT-qPCR and Western blot. RESULTS: We found that lncRNA ZNF800 was significantly more abundant in atherosclerotic plaque tissues, and substantially suppressed the proliferation and migration of VSMCs. LncRNA ZNF800 had no effect on phosphatase and tensin homolog deleted on chromosome 10 (PTEN) mRNA expression but dramatically increased the levels of PTEN protein. Enhanced lncRNA ZNF800 expression inhibited the activity of the AKT/mTOR/HIF-1α signaling pathway, downregulated the expression of vascular endothelial growth factor α (VEGF-α) and matrix metalloproteinase 1 (MMP1), and suppressed VSMC proliferation and migration. These inhibitory effects of lncRNA ZNF800 were abolished by knockdown of PTEN. The inhibitory effects of lncRNA ZNF800 on cell proliferation and migration and the expression of VEGF-α and MMP1 were exacerbated by HIF-1α knockdown in VSMCs. CONCLUSIONS: These findings demonstrated that lncRNA ZNF800 suppressed VSMC proliferation and migration by interacting with PTEN through a mechanism involving AKT/mTOR/HIF-1α signaling. Therefore, it may play a key atheroprotective role and represent a potential therapeutic target for atherosclerosis-related diseases.


Asunto(s)
MicroARNs , ARN Largo no Codificante , Movimiento Celular , Proliferación Celular , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética
7.
Inflammation ; 43(6): 2222-2231, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32621119

RESUMEN

Atherosclerosis is a progressive chronic inflammation in the arterial walls. It is believed that the deposition of low-density lipoprotein (LDL) and its damage to endothelial cells play a vital role in atherosclerosis. Oxidized LDL (Ox-LDL) was confirmed to induce endothelial cell pyroptosis which plays an important role in intima inflammation and the development of atherosclerosis, but the underlying molecular mechanism needs to be explored. Here, we showed that ox-LDL upregulated the expression of mixed lineage kinase domain-like (MLKL) protein at both the mRNA and protein levels in endothelial cells, associated with the augment of pro-caspase-1 cleavage, interleukin-1ß (IL-1ß) maturation, pro-IL-1ß production, and lactate dehydrogenase (LDH) release. Overexpression of MLKL substantially aggravated ox-LDL-induced increasing levels of caspase-1, IL-1ß, pro-IL-1ß, and LDH. MLKL-induced caspase-1 activation and IL-1ß maturation were abolished by NLR family, pyrin domain-containing 3 (NLRP3) specific inhibitor MCC950, or extracellular high potassium concentration. Our findings indicated that MLKL is essential for regulation of ox-LDL-induced pyroptosis and inflammation through the activation of NLRP3 inflammasome, and suggested that MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.


Asunto(s)
Regulación de la Expresión Génica , Inflamasomas/metabolismo , Lipoproteínas LDL/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Quinasas/metabolismo , Piroptosis , Aterosclerosis , Furanos/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Indenos/farmacología , Inflamación , Plásmidos/metabolismo , ARN Interferente Pequeño/metabolismo , Sulfonamidas/farmacología
8.
Atherosclerosis ; 293: 26-34, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31830726

RESUMEN

BACKGROUND AND AIMS: Many clinical trials have demonstrated that statins convey protective effects against atherosclerosis independent of cholesterol-lowering capacities. Other evidence indicates that pyroptosis, a type of programmed cell death, is likely involved in atherosclerosis, but the effects and mechanisms of statins on pyroptosis must be further revealed. METHODS: Here, we explored the effects and mechanisms of atorvastatin on pyroptosis in human vascular endothelial cells by quantitative real-time polymerase chain reaction and Western blot analyses. RESULTS: Atorvastatin upregulated long non-coding RNA (lncRNA) NEXN-AS1 and the expression of NEXN at both the mRNA and protein levels in a concentration- and time-dependent manner. Atorvastatin inhibited pyroptosis by decreasing the expression levels of the canonical inflammasome pathway biomarkers NLRP3, caspase-1, GSDMD, IL-1ß, and IL-18 at both the mRNA and protein levels. The promotion effects of atorvastatin on NEXN-AS1 and NEXN expression could be significantly abolished by knockdown of lncRNA NEXN-AS1 or NEXN, and its inhibitory effects on pyroptosis were also markedly offset by knock-down of lncRNA NEXN-AS1 or interference of NEXN. CONCLUSIONS: These results demonstrated that atorvastatin regulated pyroptosis via the lncRNA NEXN-AS1-NEXN pathway, which provides a new insight into the mechanism of how atorvastatin promotes non-lipid-lower effects against the development of atherosclerosis and gives new directions on how to reverse atherosclerosis.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Atorvastatina/farmacología , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Proteínas de Microfilamentos/genética , Piroptosis/efectos de los fármacos , ARN Largo no Codificante/genética , Anticolesterolemiantes/farmacología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Western Blotting , Células Cultivadas , Células Endoteliales/citología , Humanos , Inflamasomas/metabolismo , Proteínas de Microfilamentos/metabolismo , Piroptosis/genética , Transducción de Señal/efectos de los fármacos
9.
Exp Neurol ; 331: 113380, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32540359

RESUMEN

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.


Asunto(s)
Apoptosis/fisiología , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica/fisiología , Glioma/patología , Factores de Transcripción/metabolismo , Proliferación Celular/fisiología , Humanos , Oncogenes , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismo
10.
Cell Death Differ ; 26(9): 1670-1687, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30683918

RESUMEN

Atherosclerosis is a progressive, chronic inflammation in arterial walls. Long noncoding RNAs (lncRNAs) participate in inflammation, but the exact mechanism in atherosclerosis is unclear. Our microarray analyses revealed that the levels of lncRNA-FA2H-2 were significantly decreased by oxidized low-density lipoprotein (OX-LDL). Bioinformatics analyses indicated that mixed lineage kinase domain-like protein (MLKL) might be regulated by lncRNA-FA2H-2. In vitro experiments showed that lncRNA-FA2H-2 interacted with the promoter of the MLKL gene, downregulated MLKL expression, and the binding sites between -750 and 471 were necessary for lncRNA-FA2H-2 responsiveness to MLKL. Silencing lncRNA-FA2H-2 and overexpression of MLKL could activate inflammation and inhibited autophagy flux. Both lncRNA-FA2H-2 knockdown and overexpression of MLKL could significantly aggravate inflammatory responses induced by OX-LDL. We found that the 3-methyladenine (3-MA) and Atg7-shRNA enhanced inflammatory responses induced by knockdown of lncRNA-FA2H-2 and overexpression of MLKL. We demonstrated that the effects of MLKL on autophagy might be associated with a mechanistic target of rapamycin (mTOR)-dependent signaling pathways. In vivo experiments with apoE knockout mice fed a western diet demonstrated that LncRNA-FA2H-2 knockdown decreased microtubule-associated expression of microtubule-associated protein 1 light chain 3 II and lysosome-associated membrane protein 1, but increased expression of sequestosome 1 (p62), MLKL, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-6 in atherosclerotic lesions. Our findings indicated that the lncRNA-FA2H-2-MLKL pathway is essential for regulation of autophagy and inflammation, and suggested that lncRNA-FA2H-2 and MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.


Asunto(s)
Aterosclerosis/metabolismo , Autofagia/genética , Inflamación/metabolismo , Lipoproteínas LDL/metabolismo , Oxigenasas de Función Mixta/metabolismo , Proteínas Quinasas/metabolismo , ARN Largo no Codificante/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Animales , Aterosclerosis/genética , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Autofagia/efectos de los fármacos , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Secuenciación de Inmunoprecipitación de Cromatina , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Oxigenasas de Función Mixta/antagonistas & inhibidores , Oxigenasas de Función Mixta/genética , Proteínas Quinasas/genética , ARN Largo no Codificante/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Análisis de Matrices Tisulares
11.
DNA Cell Biol ; 38(6): 583-591, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30994379

RESUMEN

Atherosclerosis is a chronic vascular inflammatory disease that involves diverse cell types and circulating regulatory factors, including intercellular adhesion molecule (ICAM)-1, a proinflammatory cytokine. Lipopolysaccharides (LPS) increase ICAM-1 expression and promote cell adhesion, but the mechanism is not clear. We found that LPS induced time- and dose-regulated upregulation of ICAM-1 expression and downregulation of forkhead box protein C2 (Foxc2) expression in human umbilical vein endothelial cells (HUVECs). Overexpression of Foxc2 significantly inhibited both LPS-induced ICAM-1 expression in HUVECs and LPS-induced adhesion of THP-1 cells to HUVECs. Foxc2 siRNA dramatically increased both LPS-induced ICAM-1 expression and LPS-induced adhesion of THP-1 human monocytes cells to HUVECs. We conclude that Foxc2 inhibited LPS-induced adhesion of THP-1 cells to HUVECs by suppressing ICAM-1 expression in HUVECs.


Asunto(s)
Adhesión Celular , Factores de Transcripción Forkhead/fisiología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular/genética , Lipopolisacáridos/farmacología , ARN Mensajero/metabolismo
12.
J Clin Invest ; 129(3): 1115-1128, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30589415

RESUMEN

Noncoding RNAs are emerging as important players in gene regulation and disease pathogeneses. Here, we show that a previously uncharacterized long noncoding RNA, nexilin F-actin binding protein antisense RNA 1 (NEXN-AS1), modulates the expression of the actin-binding protein NEXN and that NEXN exerts a protective role against atherosclerosis. An expression microarray analysis showed that the expression of both NEXN-AS1 and NEXN was reduced in human atherosclerotic plaques. In vitro experiments revealed that NEXN-AS1 interacted with the chromatin remodeler BAZ1A and the 5' flanking region of the NEXN gene and that it also upregulated NEXN expression. Augmentation of NEXN-AS1 expression inhibited TLR4 oligomerization and NF-κB activity, downregulated the expression of adhesion molecules and inflammatory cytokines by endothelial cells, and suppressed monocyte adhesion to endothelial cells. These inhibitory effects of NEXN-AS1 were abolished by knockdown of NEXN. In vivo experiments using ApoE-knockout mice fed a Western high-fat diet demonstrated that NEXN deficiency promoted atherosclerosis and increased macrophage abundance in atherosclerotic lesions, with heightened expression of adhesion molecules and inflammatory cytokines, whereas augmented NEXN expression deterred atherosclerosis. Patients with coronary artery disease were found to have lower blood NEXN levels than healthy individuals. These results indicate that NEXN-AS1 and NEXN represent potential therapeutic targets in atherosclerosis-related diseases.


Asunto(s)
Aterosclerosis/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteínas de Microfilamentos/biosíntesis , Placa Aterosclerótica/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Aterosclerosis/genética , Aterosclerosis/patología , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Regulación hacia Abajo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Ratones , Ratones Noqueados para ApoE , Proteínas de Microfilamentos/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , ARN Largo no Codificante/genética , Células THP-1
13.
J Org Chem ; 73(20): 8010-5, 2008 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-18816105

RESUMEN

Photoinduced three-component reactions between tetracyanobenzene (TCNB), an aromatic olefin, and a beta-dicarbonyl compound afford products composed of the three components via formal elimination of hydrogen cyanide, leading to the vicinal dialkylation of the olefin and the alpha-alkylation of the beta-dicarbonyl compounds. It is shown that these reactions are initiated by photoinduced electron transfer (PET) from the olefin to the singlet excited TCNB and proceed by a nucleophile-olefin combination, aromatic substitution (NOCAS) reaction sequence with the enolized beta-dicarbonyl compound as a nucleophile. Therefore, aromatic olefins are suitable substrates in photo-NOCAS reactions when TCNB is used as the electron acceptor. In addition, these results show that the enol of beta-dicarbonyl compound serves as a carbon nucleophile to trap the alkene cation radical in PET reactions to lead to C-C bond formation.

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