RESUMO
RATIONALE: Unproven theories abound regarding the long-range uptake and endocrine activity of extracellular blood-borne microRNAs into tissue. In pulmonary hypertension (PH), microRNA-210 (miR-210) in pulmonary endothelial cells promotes disease, but its activity as an extracellular molecule is incompletely defined. OBJECTIVE: We investigated whether chronic and endogenous endocrine delivery of extracellular miR-210 to pulmonary vascular endothelial cells promotes PH. METHODS AND RESULTS: Using miR-210 replete (wild-type [WT]) and knockout mice, we tracked blood-borne miR-210 using bone marrow transplantation and parabiosis (conjoining of circulatory systems). With bone marrow transplantation, circulating miR-210 was derived predominantly from bone marrow. Via parabiosis during chronic hypoxia to induce miR-210 production and PH, miR-210 was undetectable in knockout-knockout mice pairs. However, in plasma and lung endothelium, but not smooth muscle or adventitia, miR-210 was observed in knockout mice of WT-knockout pairs. This was accompanied by downregulation of miR-210 targets ISCU (iron-sulfur assembly proteins)1/2 and COX10 (cytochrome c oxidase assembly protein-10), indicating endothelial import of functional miR-210. Via hemodynamic and histological indices, knockout-knockout pairs were protected from PH, whereas knockout mice in WT-knockout pairs developed PH. In particular, pulmonary vascular engraftment of miR-210-positive interstitial lung macrophages was observed in knockout mice of WT-knockout pairs. To address whether engrafted miR-210-positive myeloid or lymphoid cells contribute to paracrine miR-210 delivery, we studied miR-210 knockout mice parabiosed with miR-210 WT; Cx3cr1 knockout mice (deficient in myeloid recruitment) or miR-210 WT; Rag1 knockout mice (deficient in lymphocytes). In both pairs, miR-210 knockout mice still displayed miR-210 delivery and PH, thus demonstrating a pathogenic endocrine delivery of extracellular miR-210. CONCLUSIONS: Endogenous blood-borne transport of miR-210 into pulmonary vascular endothelial cells promotes PH, offering fundamental insight into the systemic physiology of microRNA activity. These results also describe a platform for RNA-mediated crosstalk in PH, providing an impetus for developing blood-based miR-210 technologies for diagnosis and therapy in this disease.
Assuntos
Endotélio Vascular/metabolismo , Hipertensão Pulmonar/metabolismo , Pulmão/irrigação sanguínea , MicroRNAs/metabolismo , Animais , Transplante de Medula Óssea , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/sangue , MicroRNAs/genética , Parabiose , Transdução de SinaisRESUMO
This study assessed dietary intakes, nutritional composition, and identified commonly eaten foods among Jamaicans in Florida. Dietary intake was assessed among 44 study participants to determine commonly eaten foods and nutrient composition. Weighed recipes were collected and analyzed to determine nutrient composition for traditional foods. Top foods that contributed to macronutrient and micronutrient intake were identified and adherence to dietary recommendations was evaluated. Mean daily energy intake was 2879 (SD 1179) kcal and 2242 (SD 1236) kcal for men and women respectively. Mean macronutrient intakes were above dietary recommendations for men and women. Top foods contributing to energy included rice and peas, sweetened juices, chicken, red peas soup, and hot chocolate drink. Results showed sodium intake was more than double the adequate intake estimate (1300-1500 mg). Findings highlight the need to include commonly eaten traditional foods in dietary questionnaires to accurately assess diet-related chronic disease risk. Findings have implications for risk factor intervention and prevention efforts among Jamaicans.
Assuntos
Dieta/etnologia , Emigrantes e Imigrantes/estatística & dados numéricos , Ingestão de Energia/etnologia , Adulto , Índice de Massa Corporal , Comportamento do Consumidor , Feminino , Florida/epidemiologia , Humanos , Jamaica/etnologia , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Fatores SocioeconômicosRESUMO
Information on dietary intakes of Jamaican immigrants in the United States is sparse. Understanding factors that influence diet is important since diet is associated with chronic diseases. This study examined the association between acculturation, socio-cultural factors, and dietary pattern among Jamaican immigrants in Florida. Jamaican persons 25-64 years who resided in two South Florida counties were recruited for participation. A health questionnaire that assessed acculturation, dietary pattern, and risk factors for cardiovascular disease was administered to participants. Generalized Estimating Equations were used to determine associations. Acculturation score was not significantly associated with dietary intake pattern (ß = - 0.02 p = 0.07). Age at migration was positively associated with traditional dietary pattern (ß = 0.02 p < 0.01). Persons with 12 or fewer years of education (ß = - 0.55 p < 0.001), divorced (ß = - 0.26 p = 0.001), or engaged in less physical activity (ß = - 0.07 p = 0.01) were more likely to adhere to a traditional diet. Although acculturation was not a statistically significant predictor of dietary intake, findings show the role of demographic and lifestyle characteristics in understanding factors associated with dietary patterns among Jamaicans. Findings point to the need to measure traditional dietary intakes among Jamaicans and other immigrant groups. Accurate assessment of disease risk among immigrant groups will lead to more accurate diet-disease risk assessment and development of effective intervention programs.
RESUMO
We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to 3 control subjects per case subject. 25(OH)D concentration was measured on all samples prior to, and including, the first IA positive visit. Nine polymorphisms in VDR, CYP24A, CYP27B1, GC, and RXRA were analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio = 0.93 for a 5 nmol/L difference; 95% CI 0.89, 0.97). Moreover, this association was modified by VDR rs7975232 (interaction P = 0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for type 1 diabetes.