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1.
Cell Rep ; 43(4): 114114, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38625791

RESUMO

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders.


Assuntos
Células Endoteliais , Mutação com Ganho de Função , Pulmão , Proteínas de Membrana , Animais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Camundongos , Pulmão/patologia , Pulmão/metabolismo , Linfócitos/metabolismo , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/metabolismo , Camundongos Endogâmicos C57BL , Humanos
3.
JCI Insight ; 7(17)2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-36073544

RESUMO

Lymphangiectasia, an anomalous dilation of lymphatic vessels first described in the 17th century, is frequently associated with chylous effusion, respiratory failure, and high mortality in young patients, yet the underlying molecular pathogenesis and effective treatments remain elusive. Here, we identify an unexpected causal link between MAPK activation and defective development of the lymphatic basement membrane that drives lymphangiectasia. Human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK activation within lymphatic endothelial cells. Endothelial KRASG12D-mediated sustained MAPK activation in newborn mice caused severe pulmonary and intercostal lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Pathological activation of MAPK in murine vasculature inhibited the Nfatc1-dependent genetic program required for laminin interactions, collagen crosslinking, and anchoring fibril formation, driving defective development of the lymphatic basement membrane. Treatment with ravoxertinib, a pharmacological inhibitor of MAPK, reverses nuclear-to-cytoplasmic localization of Nfatc1, basement membrane development defects, lymphangiectasia, and chyle accumulation, ultimately improving survival of endothelial KRAS mutant neonatal mice. These results reveal defective lymphatic basement membrane assembly and composition as major causes of thoracic lymphangiectasia and provide a potential treatment.


Assuntos
Células Endoteliais , Vasos Linfáticos , Animais , Membrana Basal , Células Endoteliais/fisiologia , Humanos , Sistema Linfático , Vasos Linfáticos/patologia , Camundongos , Piridonas , Pirimidinas
6.
Circ Res ; 129(1): 131-135, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34166069

RESUMO

Vascular malformations, affecting ≈1% to 1.5% of the population, comprise a spectrum of developmental patterning defects of capillaries, arteries, veins, and/or lymphatics. The majority of vascular malformations occur sporadically; however, inherited malformations exist as a part of complex congenital diseases. The malformations, ranging from birthmarks to life-threatening conditions, are present at birth, but may reveal signs and symptoms-including pain, bleeding, disfigurement, and functional defects of vital organs-in infancy, childhood, or adulthood. Vascular malformations often exhibit recurrent patterns at affected sites due to the lack of curative treatments. This review series provides a state-of-the-art assessment of vascular malformation research at basic, clinical, genetic, and translational levels.


Assuntos
Vasos Sanguíneos/anormalidades , Anormalidades Linfáticas , Vasos Linfáticos/anormalidades , Malformações Vasculares , Animais , Vasos Sanguíneos/metabolismo , Predisposição Genética para Doença , Variação Genética , Humanos , Anormalidades Linfáticas/genética , Anormalidades Linfáticas/metabolismo , Anormalidades Linfáticas/patologia , Anormalidades Linfáticas/terapia , Vasos Linfáticos/metabolismo , Fenótipo , Fatores de Risco , Malformações Vasculares/genética , Malformações Vasculares/metabolismo , Malformações Vasculares/patologia , Malformações Vasculares/terapia
8.
Cell Mol Life Sci ; 76(10): 1865-1876, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30758642

RESUMO

Hippocratic Corpus, a collection of Greek medical literature, described the functional anatomy of the lymphatic system in the fifth century B.C. Subsequent studies in cadavers and surgical patients firmly established that lymphatic vessels drain extravasated interstitial fluid, also known as lymph, into the venous system at the bilateral lymphovenous junctions. Recent advances revealed that lymphovenous valves and platelet-mediated hemostasis at the lymphovenous junctions maintain life-long separation of the blood and lymphatic vascular systems. Here, we review murine models that exhibit failure of blood-lymph separation to highlight the novel mechanisms and molecular targets for the modulation of lymphatic disorders. Specifically, we focus on the transcription factors, cofactors, and signaling pathways that regulate lymphovenous valve development and platelet-mediated lymphovenous hemostasis, which cooperate to maintain blood-lymph separation.


Assuntos
Plaquetas/metabolismo , Linfa/metabolismo , Linfangiogênese/genética , Vasos Linfáticos/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Hemostasia/genética , Humanos , Vasos Linfáticos/embriologia , Camundongos , Transdução de Sinais/genética
9.
J Clin Invest ; 128(5): 2064-2075, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29664014

RESUMO

Receptor interacting protein kinase 1 (RIPK1) has important kinase-dependent and kinase-independent scaffolding functions that activate or prevent apoptosis or necroptosis in a cell context-dependent manner. The kinase activity of RIPK1 mediates hypothermia and lethality in a mouse model of TNF-induced shock, reflecting the hyperinflammatory state of systemic inflammatory response syndrome (SIRS), where the proinflammatory "cytokine storm" has long been viewed as detrimental. Here, we demonstrate that cytokine and chemokine levels did not predict survival and, importantly, that kinase-inactive Ripk1D138N/D138N hematopoietic cells afforded little protection from TNF- or TNF/zVAD-induced shock in reconstituted mice. Unexpectedly, RIPK1 kinase-inactive mice transplanted with WT hematopoietic cells remained resistant to TNF-induced shock, revealing that a nonhematopoietic lineage mediated protection. TNF-treated Ripk1D138N/D138N mice exhibited no significant increases in intestinal or vascular permeability, nor did they activate the clotting cascade. We show that TNF administration damaged the liver vascular endothelium and induced phosphorylated mixed lineage kinase domain-like (phospho-MLKL) reactivity in endothelial cells isolated from TNF/zVAD-treated WT, but not Ripk1D138N/D138N, mice. These data reveal that the tissue damage present in this SIRS model is reflected, in part, by breaks in the vasculature due to endothelial cell necroptosis and thereby predict that RIPK1 kinase inhibitors may provide clinical benefit to shock and/or sepsis patients.


Assuntos
Endotélio Vascular/enzimologia , Fígado/enzimologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/enzimologia , Clorometilcetonas de Aminoácidos/toxicidade , Animais , Endotélio Vascular/lesões , Endotélio Vascular/patologia , Células-Tronco Hematopoéticas , Fígado/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Mutantes , Necrose , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/patologia , Fator de Necrose Tumoral alfa/toxicidade
10.
J Clin Invest ; 127(11): 4193-4206, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29035278

RESUMO

Lymphedema, the most common lymphatic anomaly, involves defective lymphatic valve development; yet the epigenetic modifiers underlying lymphatic valve morphogenesis remain elusive. Here, we showed that during mouse development, the histone-modifying enzyme histone deacetylase 3 (Hdac3) regulates the formation of both lymphovenous valves, which maintain the separation of the blood and lymphatic vascular systems, and the lymphatic valves. Endothelium-specific ablation of Hdac3 in mice led to blood-filled lymphatic vessels, edema, defective lymphovenous valve morphogenesis, improper lymphatic drainage, defective lymphatic valve maturation, and complete lethality. Hdac3-deficient lymphovenous valves and lymphatic vessels exhibited reduced expression of the transcription factor Gata2 and its target genes. In response to oscillatory shear stress, the transcription factors Tal1, Gata2, and Ets1/2 physically interacted with and recruited Hdac3 to the evolutionarily conserved E-box-GATA-ETS composite element of a Gata2 intragenic enhancer. In turn, Hdac3 recruited histone acetyltransferase Ep300 to form an enhanceosome complex that promoted Gata2 expression. Together, these results identify Hdac3 as a key epigenetic modifier that maintains blood-lymph separation and integrates both extrinsic forces and intrinsic cues to regulate lymphatic valve development.


Assuntos
Histona Desacetilases/fisiologia , Linfangiogênese , Vasos Linfáticos/enzimologia , Animais , Sequência de Bases , Sítios de Ligação , Proteína p300 Associada a E1A/metabolismo , Elementos Facilitadores Genéticos , Epigênese Genética , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Sistema Linfático/enzimologia , Camundongos Transgênicos
11.
J Biol Chem ; 290(45): 27067-27089, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26420484

RESUMO

About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-ß1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-ß1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-ß signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-ß rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-ß1 regulatory region and thereby maintains epigenetic silencing of Tgf-ß1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-ß1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.


Assuntos
Epigênese Genética , Coração Fetal/embriologia , Coração Fetal/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Animais , Padronização Corporal/genética , Padronização Corporal/fisiologia , Feminino , Coração Fetal/anormalidades , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Valvas Cardíacas/anormalidades , Valvas Cardíacas/embriologia , Valvas Cardíacas/metabolismo , Histona Desacetilases/deficiência , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Gravidez , Transdução de Sinais
12.
Hum Mol Genet ; 23(14): 3801-9, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24565863

RESUMO

Congenital heart defects often result from improper differentiation of cardiac progenitor cells. Although transcription factors involved in cardiac progenitor cell differentiation have been described, the associated chromatin modifiers in this process remain largely unknown. Here we show that mouse embryos lacking the chromatin-modifying enzyme histone deacetylase 3 (Hdac3) in cardiac progenitor cells exhibit precocious cardiomyocyte differentiation, severe cardiac developmental defects, upregulation of Tbx5 target genes and embryonic lethality. Hdac3 physically interacts with Tbx5 and modulates its acetylation to repress Tbx5-dependent activation of cardiomyocyte lineage-specific genes. These findings reveal that Hdac3 plays a critical role in cardiac progenitor cells to regulate early cardiogenesis.


Assuntos
Coração/embriologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Proteínas com Domínio T/metabolismo , Acetilação , Animais , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Células HEK293 , Coração/crescimento & desenvolvimento , Coração/fisiopatologia , Humanos , Camundongos , Camundongos Transgênicos , Transdução de Sinais
13.
Indian J Clin Biochem ; 26(1): 32-40, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22211011

RESUMO

In the present study, the cause of suspected false-positive (anomalous) values for CK-MB activity, in Indian patients investigated for ACS. Total serum CK and CK-MB activity, serum Troponin I were measured and CK-MB as a percentage of the total CK activity (%CK-MB) calculated. CK-MB was also estimated using densitometry and CK-MB mass assay. Anomalous specimens were tested for the presence of CK isoenzymes. In 22 healthy subjects, 11 male and female, the %CK-MB ranged from 3.6 to 30.2. In 11 male patients, with proven ACS, the %CK-MB was from 4.0 to 17.5. The cut off for anomalous CK-MB activity values was set as >33.0%. In 35 patients with anomalies, total CK values ranged from 39 to 231 U/L, CK-MB from 30 to 161 U/L. Investigation of CK isoenzymes, showed 10 patients had a CK-BB band, 14 an intermediate band between CK-MM and CK-MB (macro-CK type 1), 7 had a cathodal band (macro-CK type 2), and 3 had a band intermediate between CK-MB and CK-BB. This later band does not seem to have been previously reported. Against the CK-MB mass assay, the activity assay showed no correlation, in 43 patients (19 M, 24 F), Pearson coefficient (R(2)) was 0.006. The CK-MB immunoinhibition assay is better described as measuring "non-CK-MM activity." A %CK-MB activity >6% as a marker of ACS is not valid in our patient population. Laboratories should not use only CK-MB activity as a biochemical marker of ACS.

14.
Am J Clin Nutr ; 88(6): 1643-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19064526

RESUMO

BACKGROUND: The colonic bacterial flora, largely anaerobic, is believed to establish and stabilize in the first 2 y of life. OBJECTIVE: This study was undertaken to determine whether the bacterial flora of the colon undergoes further changes (succession) during childhood and adolescence. DESIGN: This cross-sectional study examined fecal samples from 130 healthy children and adolescents in the age group 2-17 y and from 30 healthy adults (median age: 42 y) residing in a single village in southern India. DNA was extracted and subjected to 16S rDNA-targeted real-time polymerase chain reaction to determine the relative predominance of Bifidobacterium genus, Bacteroides-Prevotella-Porphyromonas group, Lactobacillus acidophilus group, Eubacterium rectale, and Faecalibacterium prausnitzii. RESULTS: Bifidobacterium species and Bacteroides-Prevotella group were dominant fecal bacteria overall. E. rectale and Lactobacillus species were considerably less abundant. Clear age-related differences emerged, with a steep decline in Bifidobacterium species in adults (P < 0.0001), a steep decline of Lactobacillus species >5 y of age (P < 0.0001), an increase in Bacteroides during late adolescence and in adults (P = 0.0040), an increase in E. rectale during childhood and adolescence followed by a steep decline in adults (P < 0.0001), and a late childhood peak of F. prausnitzii with decline in adolescents and adults (P < 0.0001). CONCLUSIONS: Changes in the bacterial flora occur during childhood and adolescence characterized by reduction in Lactobacillus and Bifidobacterium species and an increase in Bacteroides, E rectale, and F. prausnitzii peaked during late childhood in this population.


Assuntos
Envelhecimento , Bactérias/classificação , Bactérias/isolamento & purificação , Colo/microbiologia , Fezes/microbiologia , Adolescente , Adulto , Distribuição por Idade , Bacteroides/classificação , Bacteroides/isolamento & purificação , Bifidobacterium/classificação , Bifidobacterium/isolamento & purificação , Criança , Pré-Escolar , Contagem de Colônia Microbiana , Estudos Transversais , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Eubacterium/classificação , Eubacterium/isolamento & purificação , Feminino , Humanos , Índia , Lactobacillus acidophilus/classificação , Lactobacillus acidophilus/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Filogenia , Reação em Cadeia da Polimerase/métodos , Especificidade da Espécie , Adulto Jovem
15.
Sci Signal ; 1(43): jc2, 2008 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-18957690

RESUMO

The hypoxia inducible factors (HIFs) and CCAAT/enhancer binding protein alpha (C/EBP alpha) are transcription factors that mediate adaptive responses to hypoxia and control aspects of energy metabolism, respectively. New evidence suggests that when HIF-1 alpha and C/EBP alpha interact, they bring about reciprocal functional changes, so that the activity of HIF-1 alpha is decreased and that of C/EBP alpha is restricted or increased in a tissue-specific manner. This Journal Club article highlights research depicting interactions between HIF-1 alpha and C/EBP alpha and discusses conditions and tissues in which this interaction might occur.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Ligação Proteica/fisiologia , Fatores de Transcrição
16.
J Pediatr Gastroenterol Nutr ; 46(5): 514-9, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18493205

RESUMO

BACKGROUND AND OBJECTIVE: The commensal bacterial flora of the colon may undergo changes during diarrhea, owing to colonization of the intestine by pathogens and to rapid intestinal transit. This study used molecular methods to determine changes in the composition of selected commensal anaerobic bacteria during and after acute diarrhea in children. MATERIALS AND METHODS: Fecal samples were obtained from 46 children with acute diarrhea in a rural community during an episode of acute diarrhea, immediately after recovery from diarrhea, and 3 months after recovery. DNA was extracted and quantitative polymerase chain reaction using SYBR green and genus- and species-specific primers targeting 16S rDNA were undertaken to quantitate the following groups of bacteria: Bifidobacterium spp., Bifidobacterium longum group, Bacteroides-Prevotella group, Bacteroides fragilis, Lactobacillus acidophilus group, Faecalibacterium prauznitzii, and Eubacterium rectale, relative to amplification of universal bacterial domain 16S rDNA. RESULTS: Bacteria belonging to the Bacteroides-Prevotella-Porphyromonas group, E rectale, L acidophilus, and F prauznitzii groups were low during acute diarrhea compared with their levels after recovery from diarrhea. The pattern was similar in rotavirus diarrhea and nonrotavirus diarrhea. Administration of amylase-resistant maize starch as adjuvant therapy was associated with lower levels of F prauznitzii at the time of recovery but did not lead to other changes in the floral pattern. CONCLUSIONS: Specific classes of fecal bacteria are lower during episodes of acute diarrhea in children than during periods of normal gastrointestinal health, suggesting specific alterations in the flora during diarrhea.


Assuntos
Bactérias/classificação , Diarreia/microbiologia , Fezes/microbiologia , Trânsito Gastrointestinal , Doença Aguda , Bactérias/genética , Bactérias/isolamento & purificação , Bacteroides/classificação , Bacteroides/genética , Bacteroides/isolamento & purificação , Sequência de Bases , Bifidobacterium/classificação , Bifidobacterium/genética , Bifidobacterium/isolamento & purificação , Pré-Escolar , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Feminino , Amplificação de Genes , Humanos , Lactente , Masculino , Filogenia , Reação em Cadeia da Polimerase/métodos , Prevotella/classificação , Prevotella/genética , Prevotella/isolamento & purificação , RNA Bacteriano/química , RNA Bacteriano/genética , Especificidade da Espécie
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