RESUMO
BACKGROUND: Marfan syndrome (MS) is a genetic disorder caused by a mutation in the fibrillin gene FBN1. Bicuspid aortic valve (BAV) is a congenital heart malformation of unknown cause. Both conditions are associated with ascending aortic aneurysm and premature death. This study examined the relationship among the secretion of extracellular matrix proteins fibrillin, fibronectin, tenascin, and vascular smooth muscle cell (VSMC) apoptosis. The role of matrix metalloproteinase (MMP)-2 in VSMC apoptosis was studied in MS aneurysm. METHODS AND RESULTS: Aneurysm tissue was obtained from patients undergoing surgery (MS: 4 M, 1 F, age 27-45 years; BAV: 3 M, 2 F, age 28-65 years). Normal aorta from subjects with nonaneurysm disease was also collected (4 M, 1 F, age 23-93 years). MS and BAV aneurysm histology showed areas of cystic medial necrosis (CMN) without inflammatory infiltrate. Immunohistochemical study of cultured MS and BAV VSMC showed intracellular accumulation and reduction of extracellular distribution of fibrillin, fibronectin, and tenascin. Western blot showed no increase in expression of fibrillin, fibronectin, or tenascin in MS or BAV VSMC and increased expression of MMP-2 in MS VSMCs. There was 4-fold increase in loss of cultured VSMC incubated in serum-free medium for 24 hours in both MS (27+/-8%) and BAV (32+/-14%) compared with control (7+/-5%). CONCLUSIONS: In MS and BAV there is alteration in both the amount and quality of secreted proteins and an increased degree of VSMC apoptosis. Up-regulation of MMP-2 might play a role in VSMC apoptosis in MS VSMC. The findings suggest the presence of a fundamental cellular abnormality in BAV thoracic aorta, possibly of genetic origin.
Assuntos
Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Valva Aórtica/anormalidades , Proteínas da Matriz Extracelular/metabolismo , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patologia , Músculo Liso Vascular/patologia , Adulto , Idoso , Aneurisma da Aorta Torácica/complicações , Apoptose , Western Blotting , Células Cultivadas , Feminino , Fibrilina-1 , Fibrilinas , Fibronectinas/análise , Fibronectinas/imunologia , Fibronectinas/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Síndrome de Marfan/complicações , Metaloproteinase 2 da Matriz/fisiologia , Proteínas dos Microfilamentos/análise , Proteínas dos Microfilamentos/imunologia , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/metabolismo , Transporte Proteico , Tenascina/análise , Tenascina/imunologia , Tenascina/metabolismoRESUMO
Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean ageâ=â24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (Pâ=â0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health.
Assuntos
Exercício Físico/fisiologia , Regulação da Expressão Gênica , Sistema Imunitário/citologia , Leucócitos/metabolismo , MicroRNAs/genética , Telômero/genética , Adulto , Teste de Esforço , Genoma Humano/genética , Humanos , Masculino , MicroRNAs/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
OBJECTIVE: We examined the association between disaster exposure, community support, and mental health outcomes in urban and nonurban participants of Galveston and Chambers counties after Hurricane Ike. The moderating effect of community support was evaluated as a protective factor relative to postdisaster mental health. METHODS: A representative population-based sample of 157 urban and 714 nonurban adults were interviewed 12 to 17 months after the hurricane about their mental health functioning, disaster exposure, and perceptions of community support. RESULTS: A series of multiple regressions demonstrated that disaster exposure was associated with mental health outcomes for both groups. The strength of the association varied across population samples.Community support moderated the association between interpersonal effects of the disaster and posttraumatic stress disorder (PTSD) and depression outcomes in nonurban participants and the association between property damage and PTSD in urban participants. CONCLUSIONS: Community support played a larger role in reducing PTSD and depression symptoms associated with the interpersonal effects of a disaster in the nonurban sample only. Communities may play a more beneficial role in the recovery process in nonurban areas that have elevated levels of injury or death attributed to a disaster.