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1.
Cardiovasc Res ; 120(3): 223-236, 2024 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-38385523

RESUMO

Endothelial cells (ECs) line the luminal surface of blood vessels and play a major role in vascular (patho)-physiology by acting as a barrier, sensing circulating factors and intrinsic/extrinsic signals. ECs have the capacity to undergo endothelial-to-mesenchymal transition (EndMT), a complex differentiation process with key roles both during embryonic development and in adulthood. EndMT can contribute to EC activation and dysfunctional alterations associated with maladaptive tissue responses in human disease. During EndMT, ECs progressively undergo changes leading to expression of mesenchymal markers while repressing EC lineage-specific traits. This phenotypic and functional switch is considered to largely exist in a continuum, being characterized by a gradation of transitioning stages. In this report, we discuss process plasticity and potential reversibility and the hypothesis that different EndMT-derived cell populations may play a different role in disease progression or resolution. In addition, we review advancements in the EndMT field, current technical challenges, as well as therapeutic options and opportunities in the context of cardiovascular biology.


Assuntos
Sistema Cardiovascular , Células Endoteliais , Humanos , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal , Transdução de Sinais , Diferenciação Celular
2.
BMJ Case Rep ; 15(12)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36526283

RESUMO

Costello syndrome (CS) is a rare genetic syndrome affecting multiple organs, generally caused by mutations of the HRAS gene, belonging to the RAS/MAPK genes family.A male patient with CS developed a painful pulsatile mass on the lateral side of the wrist. An initial ultrasonographic investigation confirmed the presence of a radial artery lesion, possibly an arterial aneurysm. On surgical resection, histological evaluation showed a tangle of vascular structures with variable calibre and abnormal wall histology. Immunohistochemical stainings revealed a very poor endothelial contribution to the central vascular wall structure. These histological observations led us to conclude we had managed an acute vascular malformation (VM) rupture, rather than a common arterial aneurysmal condition. Considering the molecular mechanisms regulated by RAS/MAPK genes, CS patients might have a higher risk of developing VMs and, in the presence of a pulsatile mass with acute onset, VM rupture should be considered.


Assuntos
Anormalidades Cardiovasculares , Síndrome de Costello , Malformações Vasculares , Humanos , Masculino , Síndrome de Costello/genética , Síndrome de Costello/patologia , Genes ras , Mutação , Malformações Vasculares/genética
3.
Eur Heart J ; 43(43): 4562-4576, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-35292818

RESUMO

AIMS: Histone H3 dimethylation at lysine 79 is a key epigenetic mark uniquely induced by methyltransferase disruptor of telomeric silencing 1-like (DOT1L). We aimed to determine whether DOT1L modulates vascular smooth muscle cell (VSMC) phenotype and how it might affect atherosclerosis in vitro and in vivo, unravelling the related mechanism. METHODS AND RESULTS: Gene expression screening of VSMCs stimulated with the BB isoform of platelet-derived growth factor led us to identify Dot1l as an early up-regulated epigenetic factor. Mouse and human atherosclerotic lesions were assessed for Dot1l expression, which resulted specifically localized in the VSMC compartment. The relevance of Dot1l to atherosclerosis pathogenesis was assessed through deletion of its gene in the VSMCs via an inducible, tissue-specific knock-out mouse model crossed with the ApoE-/- high-fat diet model of atherosclerosis. We found that the inactivation of Dot1l significantly reduced the progression of the disease. By combining RNA- and H3K79me2-chromatin immunoprecipitation-sequencing, we found that DOT1L and its induced H3K79me2 mark directly regulate the transcription of Nf-κB-1 and -2, master modulators of inflammation, which in turn induce the expression of CCL5 and CXCL10, cytokines fundamentally involved in atherosclerosis development. Finally, a correlation between coronary artery disease and genetic variations in the DOT1L gene was found because specific polymorphisms are associated with increased mRNA expression. CONCLUSION: DOT1L plays a key role in the epigenetic control of VSMC gene expression, leading to atherosclerosis development. Results identify DOT1L as a potential therapeutic target for vascular diseases.


Assuntos
Aterosclerose , Músculo Liso Vascular , Humanos , Camundongos , Animais , Músculo Liso Vascular/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Monócitos/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Aterosclerose/genética , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , Camundongos Knockout , Inativação Gênica , Células Cultivadas
4.
EMBO Mol Med ; 13(10): e14060, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34551209

RESUMO

The role of single nucleotide polymorphisms (SNPs) in the etiopathogenesis of cardiovascular diseases is well known. The effect of SNPs on disease predisposition has been established not only for protein coding genes but also for genes encoding microRNAs (miRNAs). The miR-143/145 cluster is smooth muscle cell-specific and implicated in the pathogenesis of atherosclerosis. Whether SNPs within the genomic sequence of the miR-143/145 cluster are involved in cardiovascular disease development is not known. We thus searched annotated sequence databases for possible SNPs associated with miR-143/145. We identified one SNP, rs41291957 (G > A), located -91 bp from the mature miR-143 sequence, as the nearest genetic variation to this miRNA cluster, with a minor allele frequency > 10%. In silico and in vitro approaches determined that rs41291957 (A) upregulates miR-143 and miR-145, modulating phenotypic switching of vascular smooth cells towards a differentiated/contractile phenotype. Finally, we analysed association between rs41291957 and CAD in two cohorts of patients, finding that the SNP was a protective factor. In conclusion, our study links a genetic variation to a pathological outcome through involvement of miRNAs.


Assuntos
Doença da Artéria Coronariana , MicroRNAs , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Genoma , Humanos , MicroRNAs/genética , Miócitos de Músculo Liso , Polimorfismo de Nucleotídeo Único
6.
Bone ; 140: 115571, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32768688

RESUMO

Biallelic variants in neuroblastoma-amplified sequence (NBAS) cause an extremely broad spectrum of phenotypes. Clinical features range from isolated recurrent episodes of liver failure to multisystemic syndrome including short stature, skeletal osteopenia and dysplasia, optic atrophy, and a variable immunological, cutaneous, muscular, and neurological abnormalities. Hemizygous variants in CUL4B cause syndromic X-linked intellectual disability characterized by limitations in intellectual functions, developmental delays in gait, cognitive, and speech functioning, and other features including short stature, dysmorphism, and cerebral malformations. In this study, we report on a 4.5-month-old preterm infant with a complex phenotype mainly characterized by placental-related severe intrauterine growth restriction, post-natal growth failure with spontaneous bone fractures, which led to a suspicion of osteogenesis imperfecta, and lethal bronchopulmonary dysplasia with pulmonary hypertension. Whole exome sequencing identified compound heterozygosity for a known frameshift and a novel missense variant in NBAS and hemizygosity for a known CUL4B nonsense mutation. In vitro functional studies on the novel NBAS missense substitution demonstrated altered Golgi-to-endoplasmic reticulum retrograde vesicular trafficking and reduced collagen secretion, likely explaining part of the patient's phenotype. We also provided a comprehensive overview of the phenotypic features of NBAS and CUL4B deficiency, thus updating the recently emerging NBAS genotype-phenotype correlations. Our findings highlight the power of a genome-first approach for an early diagnosis of complex phenotypes.


Assuntos
Proteínas de Neoplasias , Neuroblastoma , Proteínas Culina , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Mutação/genética , Proteínas de Neoplasias/genética , Fenótipo , Placenta , Gravidez
7.
Circ Res ; 126(12): e120-e135, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32216529

RESUMO

RATIONALE: MicroRNAs (miRNAs, miRs) are small noncoding RNAs that modulate gene expression by negatively regulating translation of target genes. Although the role of several miRNAs in vascular smooth muscle cells (VSMCs) has been extensively characterized, the function of miRNA-128-3p (miR-128) is still unknown. OBJECTIVE: To determine if miR-128 modulates VSMC phenotype and to define the underlying mechanisms. METHODS AND RESULTS: We screened for miRNAs whose expression is modulated by an altered DNA methylation status in VSMCs, and among the hits, we selected miR-128. We found that miR-128 was expressed in various tissues, primary murine cells, and pathological murine and human vascular specimens. Through gain- and loss-of-function approaches, we determined that miR-128 affects VSMC proliferation, migration, differentiation, and contractility. The alterations of those properties were dependent upon epigenetic regulation of key VSMC differentiation genes; notably, Kruppel-like factor 4 was found to be a direct target of miR-128 and able to modulate the methylation status of the pivotal VSMC gene myosin heavy chain 11 (Myh11). Finally, in vivo lentiviral delivery of miR-128 prevented intimal hyperplasia in a mouse model of carotid restenosis without modifying vital cardiovascular parameters. CONCLUSION: miR-128 is a critical modulator of VSMCs and is regulated by epigenetic modifications upon stress. Its modulation in the context of disease could be exploited for therapeutic purposes.


Assuntos
Estenose das Carótidas/metabolismo , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Animais , Estenose das Carótidas/genética , Diferenciação Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Metilação de DNA , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , MicroRNAs/genética , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo
8.
Circ Res ; 124(4): 498-510, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30582454

RESUMO

RATIONALE: microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs are involved in the modulation of miRNA activity in VSMCs is unknown. OBJECTIVE: We aimed to identify circular RNAs interacting with miRNAs enriched in VSMCs and modulating the cells' activity. METHODS AND RESULTS: RNA sequencing and bioinformatics identified several circular RNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circular RNA gemmed from alternative splicing of Lrp6 (lipoprotein receptor 6), a gene highly expressed in vessels and implicated in vascular pathologies and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITGß8 (integrin-ß8), FASCIN (fascin actin-bundling protein 1), KLF4 (Kruppel-like factor 4), Yes1 (YES proto-oncogene 1), and Lox (lysyl oxidase). The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR-145 versus unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids. CONCLUSIONS: circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.


Assuntos
MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , RNA Circular/genética , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Cadeias beta de Integrinas/genética , Cadeias beta de Integrinas/metabolismo , Fator 4 Semelhante a Kruppel , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-yes/genética , Proteínas Proto-Oncogênicas c-yes/metabolismo , RNA Circular/metabolismo
9.
J Clin Invest ; 128(6): 2473-2486, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29558369

RESUMO

Adult vascular smooth muscle cells (VSMCs) dedifferentiate in response to extracellular cues such as vascular damage and inflammation. Dedifferentiated VSMCs are proliferative, migratory, less contractile, and can contribute to vascular repair as well as to cardiovascular pathologies such as intimal hyperplasia/restenosis in coronary artery and arterial aneurysm. We here demonstrate the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as an epigenetic master regulator of VSMC plasticity. UHRF1 expression correlated with the development of vascular pathologies associated with modulation of noncoding RNAs, such as microRNAs. miR-145 - pivotal in regulating VSMC plasticity, which is reduced in vascular diseases - was found to control Uhrf1 mRNA translation. In turn, UHRF1 triggered VSMC proliferation, directly repressing promoters of cell-cycle inhibitor genes (including p21 and p27) and key prodifferentiation genes via the methylation of DNA and histones. Local vascular viral delivery of Uhrf1 shRNAs or Uhrf1 VSMC-specific deletion prevented intimal hyperplasia in mouse carotid artery and decreased vessel damage in a mouse model of aortic aneurysm. Our study demonstrates the fundamental role of Uhrf1 in regulating VSMC phenotype by promoting proliferation and dedifferentiation. UHRF1 targeting may hold therapeutic potential in vascular pathologies.


Assuntos
Aneurisma Aórtico/metabolismo , Artérias Carótidas/metabolismo , Epigênese Genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Nucleares/metabolismo , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Proteínas Estimuladoras de Ligação a CCAAT , Artérias Carótidas/patologia , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/genética , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Proteínas Nucleares/genética , Ubiquitina-Proteína Ligases
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