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1.
Cell ; 186(26): 5677-5689, 2023 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-38065099

RESUMO

RNA sequencing in situ allows for whole-transcriptome characterization at high resolution, while retaining spatial information. These data present an analytical challenge for bioinformatics-how to leverage spatial information effectively? Properties of data with a spatial dimension require special handling, which necessitate a different set of statistical and inferential considerations when compared to non-spatial data. The geographical sciences primarily use spatial data and have developed methods to analye them. Here we discuss the challenges associated with spatial analysis and examine how we can take advantage of practice from the geographical sciences to realize the full potential of spatial information in transcriptomic datasets.


Assuntos
Análise de Dados , Análise Espacial , Transcriptoma , Biologia Computacional , Perfilação da Expressão Gênica , Transcriptoma/genética
2.
J Autoimmun ; 125: 102755, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34857436

RESUMO

OBJECTIVE: Adenosine deaminase acting on RNA-1 (ADAR1) enzyme is a type I interferon (IFN)-stimulated gene (ISG) catalyzing the deamination of adenosine-to-inosine, a process called A-to-I RNA editing. A-to-I RNA editing takes place mainly in Alu elements comprising a primate-specific level of post-transcriptional gene regulation. Whether RNA editing is involved in type I IFN responses in systemic sclerosis (SSc) patients remains unknown. METHODS: ISG expression was quantified in skin biopsies and peripheral blood mononuclear cells derived from SSc patients and healthy subjects. A-to-I RNA editing was examined in the ADAR1-target cathepsin S (CTSS) by an RNA editing assay. The effect of ADAR1 on interferon-α/ß-induced CTSS expression was assessed in human endothelial cells in vitro. RESULTS: Increased expression levels of the RNA editor ADAR1, and specifically the long ADAR1p150 isoform, and its target CTSS are strongly associated with type I IFN signature in skin biopsies and peripheral blood derived from SSc patients. Notably, IFN-α/ß-treated human endothelial cells show 8-10-fold increased ADAR1p150 and 23-35-fold increased CTSS expression, while silencing of ADAR1 reduces CTSS expression by 60-70%. In SSc patients, increased RNA editing rate of individual adenosines located in CTSS 3' UTR Alu elements is associated with higher CTSS expression (r = 0.36-0.6, P < 0.05 for all). Similar findings were obtained in subjects with activated type I IFN responses including SLE patients or healthy subjects after influenza vaccination. CONCLUSION: ADAR1p150-mediated A-to-I RNA editing is critically involved in type I IFN responses highlighting the importance of post-transcriptional regulation of proinflammatory gene expression in systemic autoimmunity, including SSc.


Assuntos
Interferon Tipo I , Escleroderma Sistêmico , Adenosina/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Células Endoteliais/metabolismo , Humanos , Inosina/genética , Interferon Tipo I/metabolismo , Leucócitos Mononucleares/metabolismo , RNA , Edição de RNA , Proteínas de Ligação a RNA/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo
3.
J Mol Cell Cardiol ; 160: 111-120, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34302813

RESUMO

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo- double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.


Assuntos
Adenosina/metabolismo , Elementos Alu/genética , Aterosclerose/sangue , Doença da Artéria Coronariana/sangue , Inosina/metabolismo , Placa Aterosclerótica/sangue , Edição de RNA/genética , Estabilidade de RNA/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/genética , Sítios de Ligação , Células Cultivadas , Estudos de Coortes , Doença da Artéria Coronariana/genética , Feminino , Inativação Gênica , Ribonucleoproteína Nuclear Heterogênea D0/genética , Ribonucleoproteína Nuclear Heterogênea D0/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transfecção
4.
Atherosclerosis ; 327: 49-58, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34038763

RESUMO

BACKGROUND AND AIMS: Preclinical data suggest that the ageing-induced miR-34a regulates vascular senescence. Herein we sought to assess whether the miR-34 family members miR-34a, miR-34b and miR-34c are involved in human arterial disease. METHODS: Expression levels of miR-34a/b/c were quantified by TaqMan assay in peripheral blood mononuclear cells (PBMCs) derived from a consecutive cohort of 221 subjects who underwent cardiovascular risk assessment and thorough vascular examination for aortic stiffness and extent of arterial atherosclerosis. RESULTS: High miR-34a was independently associated with the presence of CAD [OR (95%C.I.): 3.87 (1.56-9.56); p = 0.003] and high miR-34c with the number of diseased arterial beds [OR (95%C.I.): 1.88 (1.034-3.41); p = 0.038], while concurrent high expression of miR-34-a/c or all three miR-34a/b/c was associated with aortic stiffening (miR-34a/c: p = 0.022; miR-34a/b/c: p = 0.041) and with the extent of atherosclerosis [OR (95%C.I.) for number of coronary arteries [miR-34a/c: 3.29 (1.085-9.95); miR-34a/b/c: 6.06 (1.74-21.2)] and number of diseased arterial beds [miR-34a/c: 3.51 (1.45-8.52); miR-34a/b/c: 2.89 (1.05-7.92)] after controlling for possible confounders (p < 0.05 for all). Mechanistically, the increased levels of miR-34a or miR-34c were inversely associated with expression of SIRT1 or JAG1, NOTCH2, CTNNB1 and ATF1, respectively. The association of miR-34a/c or miR-34a/b/c with CAD was mainly mediated through SIRT1 and to a lesser extent through JAG1 as revealed by generalized structural equation modeling. Leukocyte-specific ablation of miR-34a/b/c ameliorates atherosclerotic plaque development and increases Sirt1 and Jag1 expression in an atherosclerosis mouse model confirming the human findings. CONCLUSIONS: The present study reveals the clinical significance of the additive role of miR-34a/b/c in vascular ageing and atherosclerotic vascular disease.


Assuntos
Envelhecimento , Aterosclerose , MicroRNAs , Humanos , Proteína Jagged-1 , Leucócitos Mononucleares , Sirtuína 1
5.
J Am Coll Cardiol ; 75(8): 952-967, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32130931

RESUMO

Aging-related cellular and molecular processes including low-grade inflammation are major players in the pathogenesis of cardiovascular disease (CVD) and Alzheimer's disease (AD). Epidemiological studies report an independent interaction between the development of dementia and the incidence of CVD in several populations, suggesting the presence of overlapping molecular mechanisms. Accumulating experimental and clinical evidence suggests that amyloid-beta (Aß) peptides may function as a link among aging, CVD, and AD. Aging-related vascular and cardiac deposition of Αß induces tissue inflammation and organ dysfunction, both important components of the Alzheimer's disease amyloid hypothesis. In this review, the authors describe the determinants of Aß metabolism, summarize the effects of Aß on atherothrombosis and cardiac dysfunction, discuss the clinical value of Αß1-40 in CVD prognosis and patient risk stratification, and present the therapeutic interventions that may alter Aß metabolism in humans.


Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doenças Cardiovasculares/metabolismo , Doença de Alzheimer/etiologia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Humanos , Mortalidade , Medição de Risco
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