RESUMO
Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-ß signaling, and will discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.
Assuntos
Aneurisma da Aorta Torácica , Sistema Cardiovascular , Síndrome de Loeys-Dietz , Síndrome de Marfan , Tecido Conjuntivo , Humanos , Síndrome de Loeys-Dietz/genética , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fatores de Crescimento TransformadoresRESUMO
Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, heritable connective tissue syndromes related to TGF-ß receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.
Assuntos
Aneurisma da Aorta Torácica/genética , Cardiopatias Congênitas/genética , Doenças das Valvas Cardíacas/genética , Síndrome de Loeys-Dietz/genética , Síndrome de Marfan/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genética , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anticorpos Neutralizantes/farmacologia , Aneurisma da Aorta Torácica/tratamento farmacológico , Aneurisma da Aorta Torácica/patologia , Aneurisma da Aorta Torácica/cirurgia , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Doença da Válvula Aórtica Bicúspide , Regulação da Expressão Gênica , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/cirurgia , Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/cirurgia , Humanos , Síndrome de Loeys-Dietz/tratamento farmacológico , Síndrome de Loeys-Dietz/patologia , Síndrome de Loeys-Dietz/cirurgia , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/patologia , Síndrome de Marfan/cirurgia , Mutação , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteínas Smad/genética , Fator de Crescimento Transformador beta/antagonistas & inibidoresRESUMO
BACKGROUND: Maintenance of the structure and mechanical properties of the thoracic aorta contributes to aortic function and is dependent on the composition of the extracellular matrix and the cellular content within the aortic wall. Age-related alterations in the aorta include changes in cellular content and composition of the extracellular matrix; however, the precise roles of these age-related changes in altering aortic mechanical function are not well understood. METHODS AND RESULTS: Thoracic aortic rings from the descending segment were harvested from C57BL/6 mice aged 6 and 21 months. Thoracic aortic diameter and wall thickness were higher in the old mice. Cellular density was reduced in the medial layer of aortas from the old mice; concomitantly, collagen content was higher in old mice, but elastin content was similar between young and old mice. Stress relaxation, an index of compliance, was reduced in aortas from old mice and correlated with collagen fraction. Contractility of the aortic rings following potassium stimulation was reduced in old versus young mice. Furthermore, collagen gel contraction by aortic smooth muscle cells was reduced with age. CONCLUSIONS: These results demonstrate that numerous age-related structural changes occurred in the thoracic aorta and were related to alterations in mechanical properties. Aortic contractility decreased with age, likely because of a reduction in medial cell number in addition to a smooth muscle contractile deficit. Together, these unique findings provide evidence that the age-related changes in structure and mechanical function coalesce to provide an aortic substrate that may be predisposed to aortopathies.
Assuntos
Envelhecimento/patologia , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Doenças da Aorta/etiologia , Rigidez Vascular , Vasoconstrição , Vasodilatação , Fatores Etários , Envelhecimento/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Colágeno/metabolismo , Complacência (Medida de Distensibilidade) , Elastina/metabolismo , Matriz Extracelular/metabolismo , Feminino , Técnicas In Vitro , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
BACKGROUND: Thoracic aortic aneurysms (TAAs) develop through an asymptomatic process resulting in gross dilation that progresses to rupture if left undetected and untreated. If detected, patients with TAA are followed over time until the risk of rupture outweighs the risk of surgical repair. Current methodologies for tracking TAA size are limited to expensive computed tomography or magnetic resonance imaging because no acceptable population screening tools are currently available. Previous studies from this laboratory and others have identified differential protein profiles for the matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs), in ascending TAA tissue from patients with bicuspid aortic valves (BAVs), versus patients with idiopathic degenerative disease and a tricuspid aortic valve (TAV). In addition, altered microRNA (miR) expression levels have also been reported in TAAs compared with normal aortic tissue. The objective of our study was to identify circulating factors within plasma that could serve as potential biomarkers for distinguishing etiologic subtypes of aneurysm disease. METHODS: Ascending TAA tissue and plasma specimens were obtained from patients with BAV (n = 21) and TAV (n = 21) at the time of surgical resection. The protein abundance of key MMPs (1, 2, 3, 8, and 9), TIMPs (1, 2, 3, and 4), and miRs (1, 21, 29a, 133a, 143, and 145) was examined using a multianalyte protein profiling system or by quantitative polymerase chain reaction, respectively. Results were compared with normal aortic tissue and plasma obtained from patients without aortic disease (n = 10). RESULTS: Significant (P < .05) differences in standardized miR-1 and miR-21 abundance between BAV and TAV aortic tissue samples and different tissue and plasma profiles of analyte differences from normal aorta where observed between the BAV and TAV groups. Linear regression analysis revealed significant linear relationships in plasma and tissue measurements only for MMP-8 and TIMP-1, TIMP-3, and TIMP-4 (P < .05). Receiver operator curve analysis revealed specific cassettes of analytes predictive of TAA disease. Relative to normal aorta, BAV proteolytic balance was significantly increased for MMP-1, MMP-2, and MMP-7, and for decreased MMP-8 and MMP-9. In contrast, TAV proteolytic balance relative to normal aorta was significantly increased only for MMP-1 and decreased for MMP-8 and MMP-9. CONCLUSIONS: Taken together, these unique data demonstrate differential plasma profiles of MMPs, TIMPs, and miRs in ascending TAA specimens from patients with BAV and TAV. These results suggest that circulating biomarkers may form the foundation for a broader platform of biomarkers capable of detecting the presence of TAA using a simple blood test and may also be useful in personalized strategies to distinguish between etiologic subtypes of TAAs in patients with aneurysm disease.
Assuntos
Aneurisma da Aorta Torácica/sangue , Metaloproteinases da Matriz/sangue , MicroRNAs/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Aneurisma da Aorta Torácica/etiologia , Aneurisma da Aorta Torácica/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Diferencial , Humanos , Modelos Lineares , Modelos Logísticos , Valor Preditivo dos Testes , Prognóstico , Análise Serial de Proteínas , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
This article discusses the incidence, geographic differences, and risk factors for the 2 most common cancers of the esophagus: squamous cell and adenocarcinoma.