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1.
Pol J Microbiol ; 68(4): 439-447, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31880888

RESUMO

Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes - Typhimurium, Enteritidis, and Choleraesuis - in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1ß, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy - significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1ß secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1ß secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy.Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes ­ Typhimurium, Enteritidis, and Choleraesuis ­ in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1ß, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy ­ significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1ß secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1ß secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy.


Assuntos
Aneurisma Aórtico/microbiologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/patogenicidade , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/imunologia , Linhagem Celular , Humanos , Interferon-alfa/genética , Interferon-alfa/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Antígeno Ki-1/genética , Antígeno Ki-1/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Monócitos/imunologia , Monócitos/microbiologia , Plasmídeos/genética , Plasmídeos/metabolismo , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Salmonella typhimurium/genética , Salmonella typhimurium/fisiologia , Sorogrupo , Virulência
2.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 107-114, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385411

RESUMO

Marfan syndrome (MFS) is caused by mutations in the protein fibrillin-1 (FBN1) which affects the integrity of connective tissue elastic fibres. The most severe clinical outcome is the formation of ascending aortic aneurysms. FBN1 mutations are extremely variable and the prediction of disease phenotype and aortic risk is challenging under the prevailing mutation type classification. Finding a better correlation between mutation type and disease development is crucial for patient treatment. By mRNA sequencing of cultured vascular smooth muscle cells derived from control subjects and from the dilated and non-dilated aortic tunica media of MFS patients, we found a scarcely described FBN1 3'UTR mutation. This mutation was accompanied by a clear gene ontological endoplasmic reticulum (ER) stress response in the non-dilated aortic zone, which was confirmed by the increased transcriptional expression of MANF, HSPA5, SEL1L, DDIT3/CHOP and CRELD2 as well as protein expression levels of BiP/GRP78, CHOP and sXBP1. Moreover, the ER stress response was accompanied by a decrease in the phosphorylation levels of the protein translation regulator elF2α. In conclusion, we here identify a 3'UTR mutation of FBN1 in MFS patients, whose molecular mechanism suggest the involvement of the ER stress response in the formation of the aortic aneurysm. Our results emphasise the importance of mutations in non-coding regions and their resulting molecular mechanisms in the development of connective tissue diseases with impact on the cardiovascular system.


Assuntos
Regiões 3' não Traduzidas/genética , Aneurisma Aórtico/metabolismo , Estresse do Retículo Endoplasmático , Fibrilina-1/genética , Fibrilina-1/metabolismo , Síndrome de Marfan/metabolismo , Mutação , Aorta/metabolismo , Aneurisma Aórtico/genética , Moléculas de Adesão Celular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Síndrome de Marfan/genética , Músculo Liso Vascular/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas/metabolismo , RNA Mensageiro , Fatores de Risco , Fator de Transcrição CHOP/metabolismo , Regulação para Cima
3.
J Intern Med ; 285(1): 102-114, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30280445

RESUMO

BACKGROUND: An individual with a bicuspid aortic valve (BAV) runs a substantially higher risk of developing aneurysm in the ascending aorta compared to the normal population with tricuspid aortic valves (TAV). Aneurysm formation in patients with BAV and TAV is known to be distinct at the molecular level but the underlying mechanisms are undefined. Here, we investigated the still incompletely described role of microRNAs (miRNAs), important post-transcriptional regulators of gene expression, in such aortic disease of patients with BAV as compared with TAV. METHODS AND RESULTS: Using a system biology approach, based on data obtained from proteomic analysis of non-dilated aortas from BAV and TAV patients, we constructed a gene-interaction network of regulatory microRNAs associated with the observed differential protein signature. The miR-200 family was the highest ranked miRNA, hence potentially having the strongest effect on the signalling network associated with BAV. Further, qRT-PCR and ChIP analyses showed lower expression of miR-200c, higher expression of miR-200 target genes, ZEB1/ZEB2 transcription factors, and higher chromatin occupancy of the miR-200c promoter by ZEB1/ZEB2 in BAV patients, indicating a miR-200c/ZEBs negative feedback loop and induction of endothelial/epithelial mesenchymal transition (EndMT/EMT). CONCLUSION: We propose that a miR-200-dependent process of EndMT/EMT is a plausible biological mechanism rendering the BAV ascending aorta more prone to aneurysm development. Although initially supported by a miR-200c/ZEB feedback loop, this process is most probably advanced by cooperation of other miRNAs.


Assuntos
Aorta/metabolismo , Aorta/patologia , Aneurisma Aórtico/genética , Valva Aórtica/anormalidades , Transição Epitelial-Mesenquimal/genética , Doenças das Valvas Cardíacas/patologia , MicroRNAs/genética , Aneurisma Aórtico/patologia , Valva Aórtica/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Proteômica , Transdução de Sinais , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
4.
Cardiovasc Pathol ; 38: 1-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30359839

RESUMO

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), resulting in aortic aneurysm formation and dissections. Interestingly, variable aortopathy is observed even within MFS families with the same mutation. Thus, additional risk factors determine disease severity. Here, we describe a case of a 2-month-old Fbn1C1039G/+ MFS mouse with extreme aortic dilatation and increased vascular inflammation, when compared to MFS siblings, which coincided with unilateral renal cystic disease. In addition, this mouse presented with increased serum levels of creatinine, angiotensin-converting enzyme, corticosterone, macrophage chemoattractant protein-1, and interleukin-6, which may have contributed to the vascular pathology. Possibly, cystic kidney disease is associated with aneurysm progression in MFS patients. Therefore, we propose that close monitoring of the presence of renal cysts in MFS patients, during regular vascular imaging of the whole aorta trajectory, may provide insight in the frequency of cystic kidney disease and its potential as a novel indicator of aneurysm progression in MFS patients.


Assuntos
Aorta/patologia , Aneurisma Aórtico/etiologia , Fibrilina-1/genética , Doenças Renais Císticas/etiologia , Síndrome de Marfan/genética , Animais , Aorta/metabolismo , Aneurisma Aórtico/sangue , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Aortite/sangue , Aortite/etiologia , Aortite/genética , Aortite/patologia , Biomarcadores/sangue , Dilatação Patológica , Modelos Animais de Doenças , Fibrilina-1/metabolismo , Predisposição Genética para Doença , Doenças Renais Císticas/sangue , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Síndrome de Marfan/sangue , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo
5.
Vascul Pharmacol ; 114: 110-121, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29909014

RESUMO

Aortic aneurysms represent a major public health burden, and currently have no medical treatment options. The pathophysiology behind these aneurysms is complex and variable, depending on location and underlying cause, and generally involves progressive dysfunction of all elements of the aortic wall. Changes in smooth muscle behavior, endothelial signaling, extracellular matrix remodeling, and to a variable extent inflammatory signaling and cells, all contribute to the dilation of the aorta, ultimately resulting in high mortality and morbidity events including dissection and rupture. A large number of researchers have identified non-coding RNAs as crucial regulators of aortic aneurysm development, both in humans and in animal models. While most work to-date has focused on microRNAs, intriguing information has also begun to emerge regarding the role of long-non-coding RNAs. This review summarizes the currently available data regarding the involvement of non-coding RNAs in aneurysmal aortopathies. Going forward, these represent key potential therapeutic targets that might be leveraged in the future to slow or prevent aortic aneurysm formation, progression and rupture.


Assuntos
Aorta/metabolismo , Aneurisma Aórtico/metabolismo , RNA não Traduzido/metabolismo , Animais , Aorta/patologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Aneurisma Aórtico/terapia , Dilatação Patológica , Regulação da Expressão Gênica , Humanos , RNA não Traduzido/genética , Transdução de Sinais , Remodelação Vascular
6.
Physiol Genomics ; 50(11): 988-1001, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312140

RESUMO

Elastic fibers provide reversible elasticity to the large arteries and are assembled during development when hemodynamic forces are increasing. Mutations in elastic fiber genes are associated with cardiovascular disease. Mice lacking expression of the elastic fiber genes elastin ( Eln-/-), fibulin-4 ( Efemp2-/-), or lysyl oxidase ( Lox-/-) die at birth with severe cardiovascular malformations. All three genetic knockout models have elastic fiber defects, aortic wall thickening, and arterial tortuosity. However, Eln-/- mice develop arterial stenoses, while Efemp2-/- and Lox-/- mice develop ascending aortic aneurysms. We performed comparative gene array analyses of these three genetic models for two vascular locations and developmental stages to determine differentially expressed genes and pathways that may explain the common and divergent phenotypes. We first examined arterial morphology and wall structure in newborn mice to confirm that the lack of elastin, fibulin-4, or lysyl oxidase expression provided the expected phenotypes. We then compared gene expression levels for each genetic model by three-way ANOVA for genotype, vascular location, and developmental stage. We found three genes upregulated by genotype in all three models, Col8a1, Igfbp2, and Thbs1, indicative of a common response to severe elastic fiber defects in developing mouse aorta. Genes that are differentially regulated by vascular location or developmental stage in all three models suggest mechanisms for location or stage-specific disease pathology. Comparison of signaling pathways enriched in all three models shows upregulation of integrins and matrix proteins involved in early wound healing, but not of mature matrix molecules such as elastic fiber proteins or fibrillar collagens.


Assuntos
Aorta/embriologia , Aorta/fisiopatologia , Tecido Elástico/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Animais Recém-Nascidos , Aorta/crescimento & desenvolvimento , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/genética , Artérias/anormalidades , Colágeno Tipo VIII/genética , Modelos Animais de Doenças , Elastina/genética , Proteínas da Matriz Extracelular/genética , Feminino , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Instabilidade Articular/etiologia , Instabilidade Articular/genética , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteína-Lisina 6-Oxidase/genética , Dermatopatias Genéticas/etiologia , Dermatopatias Genéticas/genética , Trombospondina 1/genética , Malformações Vasculares/etiologia , Malformações Vasculares/genética
7.
Int J Cardiol ; 273: 230-236, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30297190

RESUMO

BACKGROUND: To determine the impact of circulating miRNA and protein activity on the severity of ascending aortic dilatation in patients with bicuspid (BAV) and tricuspid aortic valve (TAV). METHODS: By reverse transcription polymerase chain reaction, exosomal circulating expression levels (versus healthy aorta) of miRNAs and absolute levels of transforming growth factor ß (TGF-ß), matrix metalloproteinases (MMP-2, -3 and -9), tissue inhibitors (TIMP-1, -2, -3 and -4), and soluble receptors for advanced glycation end products AGEs (sRAGE) were evaluated in ascending dilated aortas of 71 patients with different valve morphotype. RESULTS: Less-dilated ascending aorta exhibited a specific miRNA signature (i.e., miR-126 miR-15b, miR-195, miR-221, miR24, miR-30b and miR-320a), which was statistically different from that of severely-dilated ascending aorta. Among these analytes, miR-15b was the most significant (p < 0.001) and resulted as an independent predictor of aortic dilatation (ß = -1.099, p = 0.041). When patients were grouped according to aortic valve morphology, miRNAs and protein proteolytic activity were different between BAV and TAV in the expression level of miR-133a, miR-155, miR-320a, miR-34a(#000425), miR-34a(#000426), miR-494 and measurements of TGF-ß and MMP-3, MMP-9, TIMP-4. The circulating level of miR-34a(#000426) was negatively correlated to the aortic wall elasticity of bicuspid patients (R = -0.653 and p = 0.011), suggesting an apparent different mechanism of aortic wall degeneration specific for BAV. CONCLUSIONS: Taken these biomarkers together, we demonstrated that the severity of aortic size and valve morphology differently modulates miRNA analytes and protein proteolytic activity in patients with ascending aortic dilatation, and this may be useful to design new therapies that inhibit miRNAs.


Assuntos
Aneurisma Aórtico/genética , Valva Aórtica/anormalidades , Exossomos/genética , Perfilação da Expressão Gênica/métodos , Doenças das Valvas Cardíacas/genética , MicroRNAs/genética , Valva Tricúspide/anormalidades , Adulto , Idoso , Aorta/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/metabolismo , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/metabolismo , Biomarcadores/metabolismo , Estudos de Coortes , Feminino , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Valva Tricúspide/diagnóstico por imagem
8.
Sci Rep ; 8(1): 14044, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232383

RESUMO

Hypothermia has been reported to be effective in protecting the brain in various clinical conditions, including resuscitation after cardiac arrest and complex cardiovascular surgery, and is considered to be a promising therapy for stroke. The present study aimed to confirm the pivotal role that miRNA-194-5p plays in deep hypothermia circulation arrest. On the basis of reductions in expression of miR-194-5p in the circulation of 21 aortic dissection patients who underwent deep hypothermia circulatory arrest, the specific expression, target, and function of miR-194-5p was investigated using primary neuron culture, polymerase chain reaction, in situ hybridization, and flow cytometry methods. Our results showed that miR-194-5p expression was significantly downregulated in hypothermia oxygen glucose deprivation-treated neurons in vitro. Cortical neurons transfected with miR-194-5p mimic exhibited increased death due to oxygen-glucose deprivation. MiR-194-5p mediated the regulation of neuronal death, which involves the downregulation of the specific target protein SUMO2, which is crucial to ischemia tolerance. Collectively, these data highlight the unique role of miR-194-5p in mediating the deep hypothermia circulation arrest response via the regulation of SUMO2. These findings suggest that miR-194-5p could be a potential therapeutic target for intervention in ischemic disease.


Assuntos
Aneurisma Dissecante/terapia , Aneurisma Aórtico/terapia , Parada Circulatória Induzida por Hipotermia Profunda/métodos , Regulação para Baixo , MicroRNAs/sangue , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Adulto , Aneurisma Dissecante/genética , Aneurisma Dissecante/metabolismo , Aneurisma Aórtico/genética , Aneurisma Aórtico/metabolismo , Sobrevivência Celular , Células Cultivadas , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/química , Neurônios/citologia , Método Simples-Cego , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo
9.
Trends Mol Med ; 24(10): 825-837, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30213701

RESUMO

Lentiviral vectors (LVs) transduce quiescent cells and provide stable integration to maintain transgene expression. Several approaches have been adopted to optimize LV safety profiles. Similarly, LV targeting has been tailored through strategies including the modification of envelope components, the use of specific regulatory elements, and the selection of appropriate administration routes. Models of aortic disease based on a single injection of pleiotropic LVs have been developed that efficiently transduce the three aorta layers in wild type mice. This approach allows the dissection of pathways involved in aortic aneurysm formation and the identification of targets for gene therapy in aortic diseases. LVs provide a fast, efficient, and affordable alternative to genetically modified mice to study disease mechanisms and develop therapeutic tools.


Assuntos
Proteína ADAMTS1/genética , Aneurisma Aórtico/terapia , Terapia Genética/métodos , Vetores Genéticos/química , Lentivirus/genética , Proteína ADAMTS1/antagonistas & inibidores , Proteína ADAMTS1/imunologia , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/imunologia , Aneurisma Aórtico/patologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Regulação da Expressão Gênica , Vetores Genéticos/imunologia , Humanos , Imunidade Inata , Lentivirus/imunologia , Camundongos , Segurança do Paciente , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução Genética/métodos , Transgenes
10.
Hum Mutat ; 39(12): 1875-1884, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30157302

RESUMO

SMAD2 is a downstream effector in the TGF-ß signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Patients 1 and 2 presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature, and poor weight gain. Patient 3 was a fetus with complex CHD and heterotaxy. The fourth patient is an adult female with aortic root aneurysm and physical features suggestive of a connective tissue disorder. WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2. We compare the phenotypes and genotypes in our patients with previously reported cases. Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities.


Assuntos
Aneurisma Aórtico/genética , Cardiopatias Congênitas/genética , Mutação , Proteína Smad2/genética , Adulto , Criança , Pré-Escolar , Exoma , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Fenótipo , Gravidez , Sequenciamento Completo do Exoma/métodos
11.
Cardiovasc Pathol ; 35: 12-19, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29729633

RESUMO

Thrombospondin 4 (TSP-4) expression is induced in the heart and vasculature under pathological conditions, including myocardial infarction, myocardial pressure overload, and hypertension. TSP-4 is linked to remodelling processes, where it may affect extracellular matrix protein organization. In previous work, we studied the role of TSP-4 in small arteries during hypertension using Ang II-treated Thrombospondin 4 knockout (Thbs4-/-) mice. We reported increased heart weight, as well as the occurrence of aortic aneurysms in the Ang II-treated Thbs4-/- animals. In the present study, we further characterized the hearts and aortas from these animals. Hypertrophy of cardiomyocytes, together with perivascular fibrosis and inflammation was observed in the Ang II-treated Thbs4-/- hearts. In the aortas, an increase in the aortic wall cross-sectional area (CSA) and wall thickness of the Ang II-treated Thbs4-/- mice was found. More detailed investigation of the Ang II-treated Thbs4-/- aortas also revealed the appearance of aortic dissections in the outer medial layer of the arteries, as well as pronounced inflammation. No differences were found in several other extracellular matrix-related parameters, such as number of elastin breaks or stress-strain relationships. However, at the ultrastructural level, collagen fibers showed alterations in diameter in the media and adventitia of the Ang II-treated Thbs4-/- mice, in the area prone to dissection. In conclusion, we identified TSP-4 as an important protein in the development of cardiac hypertrophy and aortic dissections in Ang II-induced hypertension.


Assuntos
Aneurisma Dissecante/metabolismo , Angiotensina II , Aneurisma Aórtico/metabolismo , Cardiomegalia/metabolismo , Hipertensão/metabolismo , Trombospondinas/metabolismo , Remodelação Vascular , Remodelação Ventricular , Aneurisma Dissecante/induzido quimicamente , Aneurisma Dissecante/genética , Aneurisma Dissecante/patologia , Animais , Aorta/metabolismo , Aorta/ultraestrutura , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/patologia , Dilatação Patológica , Modelos Animais de Doenças , Colágenos Fibrilares/metabolismo , Colágenos Fibrilares/ultraestrutura , Fibrose , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/patologia , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Trombospondinas/deficiência , Trombospondinas/genética
12.
Cardiovasc Res ; 114(13): 1764-1775, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800106

RESUMO

Aims: Angiotensin-II (Ang-II) is the main effector peptide of the renin-angiotensin system (RAS) and promotes leucocyte adhesion to the stimulated endothelium. Because RAS activation and Ang-II signalling are implicated in metabolic syndrome (MS) and abdominal aortic aneurysm (AAA), we investigated the effect of Ang-II on CXCL16 arterial expression, the underlying mechanisms, and the functional role of the CXCL16/CXCR6 axis in these cardiometabolic disorders. Methods and results: Results from in vitro chamber assays revealed that CXCL16 neutralization significantly inhibited mononuclear leucocyte adhesion to arterial but not to venous endothelial cells. Flow cytometry and immunofluorescence studies confirmed that Ang-II induced enhanced endothelial CXCL16 expression, which was dependent on Nox5 up-regulation and subsequent RhoA/p38-MAPK/NFκB activation. Flow cytometry analysis further showed that MS patients had higher levels of platelet activation and a higher percentage of circulating CXCR6-expressing platelets, CXCR6-expressing-platelet-bound neutrophils, monocytes, and CD8+ lymphocytes than age-matched controls, leading to enhanced CXCR6/CXCL16-dependent adhesion to the dysfunctional (Ang-II- and TNFα-stimulated) arterial endothelium. Ang-II-challenged apolipoprotein E-deficient (apoE-/-) mice had a higher incidence of AAA, macrophage, CD3+, and CXCR6+ cell infiltration and neovascularization than unchallenged animals, which was accompanied by greater CCL2, CXCL16, and VEGF mRNA expression within the lesion together with elevated levels of circulating soluble CXCL16. Significant reductions in these parameters were found in animals co-treated with the AT1 receptor antagonist losartan or in apoE-/- mice lacking functional CXCR6 receptor (CXCR6GFP/GFP). Conclusion: CXCR6 expression on platelet-bound monocytes and CD8+ lymphocytes may constitute a new membrane-associated biomarker for adverse cardiovascular events. Moreover, pharmacological modulation of this axis may positively affect cardiovascular outcome in metabolic disorders linked to Ang-II.


Assuntos
Angiotensina II , Aneurisma Aórtico/metabolismo , Plaquetas/metabolismo , Quimiocina CXCL16/metabolismo , Células Endoteliais/metabolismo , Leucócitos/metabolismo , Síndrome Metabólica/metabolismo , Receptores CXCR6/metabolismo , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/genética , Aneurisma Aórtico/prevenção & controle , Plaquetas/efeitos dos fármacos , Estudos de Casos e Controles , Adesão Celular , Células Cultivadas , Quimiocina CXCL16/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Leucócitos/efeitos dos fármacos , Masculino , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/genética , Síndrome Metabólica/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Ativação Plaquetária , Receptores CXCR6/deficiência , Receptores CXCR6/genética , Transdução de Sinais
13.
Curr Drug Targets ; 19(11): 1276-1288, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29749311

RESUMO

Aortic aneurysms represent a significant clinical problem as they largely go undetected until a rupture occurs. Currently, an understanding of mechanisms leading to aneurysm formation is limited. Numerous studies clearly indicate that vascular smooth muscle cells play a major role in the development and response of the vasculature to hemodynamic changes and defects in these responses can lead to aneurysm formation. The LDL receptor-related protein 1 (LRP1) is major smooth muscle cell receptor that has the capacity to mediate the endocytosis of numerous ligands and to initiate and regulate signaling pathways. Genetic evidence in humans and mouse models reveal a critical role for LRP1 in maintaining the integrity of the vasculature. Understanding the mechanisms by which this is accomplished represents an important area of research, and likely involves LRP1's ability to regulate levels of proteases known to degrade the extracellular matrix as well as its ability to modulate signaling events.


Assuntos
Aneurisma Aórtico/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Peptídeo Hidrolases/metabolismo , Animais , Aneurisma Aórtico/metabolismo , Modelos Animais de Doenças , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Miócitos de Músculo Liso/metabolismo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais
14.
Matrix Biol ; 71-72: 128-143, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29656146

RESUMO

Aortic aneurysms are morbid conditions that can lead to rupture or dissection and are categorized as thoracic (TAA) or abdominal aortic aneurysms (AAA) depending on their location. While AAA shares overlapping risk factors with atherosclerotic cardiovascular disease, TAA exhibits strong heritability. Human genetic studies in the past two decades have successfully identified numerous genes involved in both familial and sporadic forms of aortic aneurysm. In this review we will discuss the genetic basis of aortic aneurysm, focusing on the extracellular matrix and how insights from these studies have informed our understanding of human biology and disease pathogenesis.


Assuntos
Aneurisma Aórtico/genética , Matriz Extracelular/genética , Transdução de Sinais , Animais , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Torácica/genética , Predisposição Genética para Doença , Humanos , Mutação , Fator de Crescimento Transformador beta/genética
15.
Dev Cell ; 45(2): 226-244.e8, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29689197

RESUMO

Nuclei are actively positioned and anchored to the cytoskeleton via the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. We identified mutations in the Parkin-like E3 ubiquitin ligase Ariadne-1 (Ari-1) that affect the localization and distribution of LINC complex members in Drosophila. ari-1 mutants exhibit nuclear clustering and morphology defects in larval muscles. We show that Ari-1 mono-ubiquitinates the core LINC complex member Koi. Surprisingly, we discovered functional redundancy between Parkin and Ari-1: increasing Parkin expression rescues ari-1 mutant phenotypes and vice versa. We further show that rare variants in the human homolog of ari-1 (ARIH1) are associated with thoracic aortic aneurysms and dissections, conditions resulting from smooth muscle cell (SMC) dysfunction. Human ARIH1 rescues fly ari-1 mutant phenotypes, whereas human variants found in patients fail to do so. In addition, SMCs obtained from patients display aberrant nuclear morphology. Hence, ARIH1 is critical in anchoring myonuclei to the cytoskeleton.


Assuntos
Aneurisma Aórtico/patologia , Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Mutação , Miócitos de Músculo Liso/patologia , Ubiquitina-Proteína Ligases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/metabolismo , Proteínas de Transporte/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Pré-Escolar , Citoesqueleto , Proteínas de Drosophila/genética , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Linhagem , Fenótipo , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
16.
Int J Cardiol ; 257: 358-365, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29506732

RESUMO

The concept "common presentation of rare diseases" implies that rare diseases are masked by common phenotypic manifestations. This concept applies to both aneurysmal and valvular diseases that can be syndromic and non-syndromic. Syndromic disorders include genetic connective tissue diseases and chromosomal disorders that are diagnosed independently from the aneurysm or valve disease. Non-syndromic diseases, on the other hand, are defined by the presence of aneurysm or valve disease or both. The reasons for suspecting these rare diseases include young age, the absence of risk factors, a positive family history for aortic or valvular disease/event, and extra-cardiovascular traits for syndromes. The probands should receive genetic counseling, genetic testing [single gene in case of precise phenotyping addressing the gene to be tested, or multigene panels, in case of diseases with genetic heterogeneity], post-test counseling, clinical family screening and cascade genetic testing in relatives after the identification of a causative mutation. Segregation studies are essential in case of novel mutations, in particular non-truncation predicting variants. Clinical family screening of syndromic diseases is facilitated by the evaluation of non-cardiovascular traits; this supports early diagnosis and geno-phenotype correlation. Vice versa, family screening studies in non-syndromic aneurysmal and valvular diseases exclusively relies on CV imaging screening of relatives. In this context, conditions such as BAV and related aortopathy are easy to diagnose because BAV is present at birth while aortopathy usually develops during the life course.


Assuntos
Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/genética , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/genética , Doenças Raras/diagnóstico por imagem , Doenças Raras/genética , Testes Genéticos/métodos , Humanos , Linhagem
17.
J Vasc Surg ; 68(3): 701-711, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29510914

RESUMO

OBJECTIVE: The contemporary practice of testing for genetically triggered aortic and arterial aneurysms and dissections is not well described. This study aimed to describe this practice at a tertiary care academic center and to ascertain the yield of testing in establishing the diagnosis in patients referred on the basis of clinical suspicion. METHODS: This is a retrospective cohort study of patients referred for vascular genetic testing at an academic medical center between 2010 and 2015. Patients were identified by Current Procedural Terminology diagnostic codes 81405, 81408, and 81479 for genetic testing (Marfan syndrome, Loeys-Dietz syndrome, aneurysms-osteoarthritis syndrome, COL3A1, and familial thoracic aortic aneurysm panel [ACTA2, COL3A1, TGFBR1, TGFBR2, SMAD3, TGFB2, MYLK, MYH11, and PRKG1 genes]) and by review of the collagen vascular laboratory database for genetic testing results. Data abstracted included demographics, clinical history, reason for referral, family history, referring provider type, and outcomes of genetic testing. RESULTS: Ninety-six patients (44.3% male; median age, 40.8 years) were referred for suspected genetic vascular disease. Genetic testing was performed in 75 cases thought to have heritable mutations related to aortic or arterial aneurysms and dissections. The most common reason for genetic testing was a personal history of aortic or arterial aneurysms and dissections (62.3%; mean age, 45.8 ± 11.1 years), followed by a family history of aortic or arterial aneurysms and dissections without a personal history (26.6%; age, 28.8 ± 17.9 years). The most common genetic testing performed was a familial thoracic aortic aneurysm gene panel (44%), followed by single gene testing for vascular Ehlers-Danlos syndrome (33.3%). Genetic testing identified a pathogenic mutation in 36% of the cases. The highest likelihood of identifying a pathogenic mutation was in those who had a family history with an already diagnosed mutation (57.1%), followed by patients with aortic root and ascending aortic aneurysm or dissection (42.3%). CONCLUSIONS: In patients with suspected genetically triggered vascular disease, the yield of clinical vascular genetic testing is reasonable when selective genetic testing is performed on the basis of personal or family history. These tests should be obtained with appropriate expertise in genetic counseling and interpretation of genetic testing results. Negative genetic test results in the setting of a positive family history demonstrate the limits of testing and known mutations leading to genetically triggered aortic and arterial aneurysms and dissections and support the need for novel gene discovery.


Assuntos
Aneurisma Dissecante/genética , Aneurisma Aórtico/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Padrões de Prática Médica , Centros Médicos Acadêmicos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto Jovem
18.
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 , 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
19.
J Cardiovasc Pharmacol ; 71(4): 215-222, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29300219

RESUMO

INTRODUCTION: Available evidence suggests that the renin-angiotensin-aldosterone (RAA) system is a good target for medical intervention on aortic root dilatation in Marfan syndrome (MFS). The effect of Compound 21 (C21), a nonpeptide angiotensin II type 2 receptor agonist, on aneurysm progression was tested. METHODS: Mice with a mutation in fibrillin-1 (Fbn1) and wild-type mice were treated with vehicle, losartan, C21, enalapril, or a combination. Blood pressure, aortic root diameter, and histological slides were evaluated. RESULTS: All groups had a comparable blood pressure. Echographic evaluation of the aortic root diameter revealed a protective effect of angiotensin II type 1 receptor antagonist (losartan) and no effect of C21 treatment. None of the treatments had a beneficial effect on the histological changes in MFS. DISCUSSION: This study confirms that angiotensin II type 1 receptor antagonism (losartan) decreases aortic aneurysm growth in a mouse model of MFS. A nonpeptide angiotensin II type 2 receptor agonist (C21), at the doses studied, was ineffective. Future studies are warranted to further elucidate the exact role of the RAA system in aneurysm formation in MFS and identify alternative targets for intervention.


Assuntos
Aorta/efeitos dos fármacos , Aneurisma Aórtico/prevenção & controle , Síndrome de Marfan/tratamento farmacológico , Receptor Tipo 2 de Angiotensina/agonistas , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aorta/patologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Ecocardiografia , Fibrilina-1/genética , Losartan/farmacologia , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Receptor Tipo 2 de Angiotensina/metabolismo
20.
J Am Heart Assoc ; 7(2)2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343476

RESUMO

BACKGROUND: Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin-6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin-6 in macrophages in pathogenesis of AD. METHODS AND RESULTS: We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild-type (WT) mice, but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction. CONCLUSIONS: These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.


Assuntos
Aneurisma Dissecante/metabolismo , Aorta/metabolismo , Aneurisma Aórtico/metabolismo , Macrófagos/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Remodelação Vascular , Aneurisma Dissecante/induzido quimicamente , Aneurisma Dissecante/genética , Aneurisma Dissecante/patologia , Angiotensinas , Animais , Aorta/patologia , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Cloreto de Cálcio , Diferenciação Celular , Proliferação de Células , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Redes Reguladoras de Genes , Humanos , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas/deficiência , Proteína 3 Supressora da Sinalização de Citocinas/genética , Fatores de Tempo , Transcriptoma
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