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Environ Epidemiol ; 5(2): e143, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33870015


Exposure to higher levels of ambient air pollution is a known risk factor for cardiovascular disease but long-term effects of pollution exposure on the pulmonary vessels are unknown. Methods: Among 2428 Framingham Heart Study participants who underwent chest computed tomography (CT) between 2008 and 2011, pulmonary vascular volumes were calculated by image analysis, including the total vascular volume and small vessel volume (cross-sectional area <5 mm2; BV5 defined as small vessel volume). Using spatiotemporal models and participant home address, we assigned 1-year (2008) and 5-year (2004-2008) average concentrations of fine particulate matter (PM2.5), elemental carbon (EC), and ground-level ozone (O3), and distance to major roadway. We examined associations of 1- and 5-year exposures, and distance to road, with CT vascular volumes using multivariable linear regression models. Results: There was a consistent negative association of higher O3 with lower small vessel volumes, which persisted after adjustment for distance to road. Per interquartile range (IQR) of 2008 O3, BV5 was 0.34 mL lower (95% confidence intervals [CI], -0.61 to -0.06; P = 0.02), with similar results for 5-year exposure. One-year EC exposure and closer proximity to road were weakly associated with small vessel volumes; BV5 was 0.18 mL higher per IQR of 2008 EC (95% CI, -0.05 to 0.42; P = 0.13) and 0.40 mL higher per IQR closer proximity to road (95% CI: -0.10 to 0.89; P = 0.12). PM2.5 was not associated with small vascular volumes; BV5 was 0.26 mL lower per IQR of 2008 PM2.5 (95% CI: -0.68 to 0.16; P = 0.22). Conclusions: Among community-dwelling adults living in the northeastern United States, higher exposure to O3 was associated with lower small pulmonary vessel volumes on CT.

Circ Res ; 120(12): 1903-1915, 2017 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-28461455


RATIONALE: Mutations in ACTA2, encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. OBJECTIVE: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. METHODS AND RESULTS: Acta2-/- mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in Acta2-/- aortas or kidneys. Aortic tissue and explanted smooth muscle cells from Acta2-/- aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. CONCLUSIONS: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.

Actinas/deficiência , Angiotensina II/metabolismo , Aorta Torácica/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Receptor Tipo 1 de Angiotensina/biossíntese , Actinas/efeitos dos fármacos , Actinas/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Células Cultivadas , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/genética
Gastrointest Endosc ; 84(3): 460-6, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26972022


BACKGROUND AND AIMS: The optimal type of stent for the palliation of malignant biliary obstruction in patients with pancreatic adenocarcinoma undergoing neoadjuvant chemoradiotherapy with curative intent is unknown. We performed a prospective trial comparing 3 types of biliary stents-fully covered self-expandable metal (fcSEMS), uncovered self-expandable metal (uSEMS), and plastic-to determine which best optimized cost-effectiveness and important clinical outcomes. METHODS: In this prospective randomized trial, consecutive patients with malignant biliary obstruction from newly diagnosed pancreatic adenocarcinoma who were to start neoadjuvant chemoradiotherapy were randomized to receive fcSEMSs, uSEMSs, or plastic stents during the index ERCP. The primary outcomes were time to stent occlusion, attempted surgical resection, or death after the initiation of neoadjuvant therapy, and the secondary outcomes were total patient costs associated with the stent, including the index ERCP cost, downstream hospitalization cost due to stent occlusion, and the cost associated with procedural adverse event. RESULTS: Fifty-four patients were randomized and reached the primary end point: 16 in the fcSEMS group, 17 in the uSEMS group, and 21 in the plastic stent group. No baseline demographic or tumor characteristic differences were noted among the groups. The fcSEMSs had a longer time to stent occlusion compared with uSEMSs and plastic stents (220 vs 74 and 76 days, P < .01), although the groups had equivalent rates of stent occlusion, attempted surgical resection, and death. Although SEMS placement cost more during the index ERCP (uSEMS = $24,874 and fcSEMS = $22,729 vs plastic = $18,701; P < .01), they resulted in higher procedural AE costs per patient (uSEMS = $5522 and fcSEMS = $12,701 vs plastic = $0; P < .01). Conversely, plastic stents resulted in an $11,458 hospitalization cost per patient due to stent occlusion compared with $2301 for uSEMSs and $0 for fcSEMSs (P < .01). CONCLUSIONS: In a prospective trial comparing fcSEMSs, uSEMSs, and plastic stents for malignant biliary obstruction in patients undergoing neoadjuvant therapy with curative intent for pancreatic adenocarcinoma, no stent type was superior in optimizing cost-effectiveness, although fcSEMSs resulted in fewer days of neoadjuvant treatment delay and a longer time to stent occlusion. (Clincial trial registration number: NCT01038713.).

Adenocarcinoma/terapia , Quimiorradioterapia , Colestase/cirurgia , Terapia Neoadjuvante , Neoplasias Pancreáticas/terapia , Stents Metálicos Autoexpansíveis , Adenocarcinoma/complicações , Idoso , Colangiopancreatografia Retrógrada Endoscópica/economia , Colangiopancreatografia Retrógrada Endoscópica/instrumentação , Colestase/etiologia , Análise Custo-Benefício , Feminino , Humanos , Masculino , Metais/economia , Pessoa de Meia-Idade , Neoplasias Pancreáticas/complicações , Plásticos/economia , Stents Metálicos Autoexpansíveis/economia , Stents/economia , Resultado do Tratamento , Estados Unidos
Hum Mol Genet ; 22(15): 3123-37, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23591991


Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α-actin (α-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown. Here, we show that the loss of Acta2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. Acta2(-/-) mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of α-SMA induced hyperplasia through focal adhesion (FA) rearrangement, FA kinase activation, re-localization of p53 from the nucleus to the cytoplasm and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-ß). Disruption of α-SMA in wild-type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-ß activation and Acta2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-ß, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.

Actinas/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Actinas/genética , Animais , Movimento Celular/genética , Núcleo Celular/metabolismo , Proliferação de Células , Ativação Enzimática , Hiperplasia , Camundongos , Camundongos Knockout , Modelos Biológicos , Fenótipo , Transporte Proteico , Espécies Reativas de Oxigênio/metabolismo
Circ Res ; 110(11): 1411-22, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22511748


RATIONALE: Mutations in myosin heavy chain (MYH11) cause autosomal dominant inheritance of thoracic aortic aneurysms and dissections. At the same time, rare, nonsynonymous variants in MYH11 that are predicted to disrupt protein function but do not cause inherited aortic disease are common in the general population and the vascular disease risk associated with these variants is unknown. OBJECTIVE: To determine the consequences of the recurrent MYH11 rare variant, R247C, through functional studies in vitro and analysis of a knock-in mouse model with this specific variant, including assessment of aortic contraction, response to vascular injury, and phenotype of primary aortic smooth muscle cells (SMCs). METHODS AND RESULTS: The steady state ATPase activity (actin-activated) and the rates of phosphate and ADP release were lower for the R247C mutant myosin than for the wild-type, as was the rate of actin filament sliding in an in vitro motility assay. Myh11(R247C/R247C) mice exhibited normal growth, reproduction, and aortic histology but decreased aortic contraction. In response to vascular injury, Myh11(R247C/R247C) mice showed significantly increased neointimal formation due to increased SMC proliferation when compared with the wild-type mice. Primary aortic SMCs explanted from the Myh11(R247C/R247C) mice were dedifferentiated compared with wild-type SMCs based on increased proliferation and reduced expression of SMC contractile proteins. The mutant SMCs also displayed altered focal adhesions and decreased Rho activation, associated with decreased nuclear localization of myocardin-related transcription factor-A. Exposure of the Myh11(R247C/R247C) SMCs to a Rho activator rescued the dedifferentiated phenotype of the SMCs. CONCLUSIONS: These results indicate that a rare variant in MYH11, R247C, alters myosin contractile function and SMC phenotype, leading to increased proliferation in vitro and in response to vascular injury.

Músculo Liso Vascular/metabolismo , Mutação , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Vasoconstrição , Trifosfato de Adenosina/metabolismo , Animais , Aorta/metabolismo , Sítios de Ligação , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Adesões Focais/metabolismo , Adesões Focais/patologia , Técnicas de Introdução de Genes , Genótipo , Cinética , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Cadeias Pesadas de Miosina/genética , Fenótipo , Transativadores/metabolismo , Transfecção , Vasoconstrição/genética , Proteínas rho de Ligação ao GTP/metabolismo