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
Ant gardens are a special association type between ants and epiphytes, in which two or more ant species can share the same nest in a parabiotic relationship. This association that occurs in tropical forests is still poorly understood. The aim of this study was to evaluate ants gardens in the Central Amazon and to determine if ants identify and remove potential herbivores that are visiting the host tree of ants gardens occupied by the species Camponotus femoratus and Crematogaster levior. In this study, it was observed 42 trees occupied by ants gardens. In each tree it was inserted a termite as bait at different distances from the nest, the time of the termites' removal was recorded and it was observed if there was the need of assistance from other ants to perform the removal of the bait. The results revealed that both species examined the tree host to forage. During the capture of the bait, C. levior was more efficient to detect the termite, and it was not observed the need of recruits to carry it to the nest. In some cases, individuals of de C. femoratus identified the bait and individuals of C. levior carried to the nest. The relationship between the host tree and ants is beneficial to both of them, since the tree receives indirect protection against termites and gives support to the ants nest.(AU)
Jardins de formigas são um tipo especial de associação entre formigas e epífitas, em que duas ou mais espécies de formigas podem compartilhar o mesmo ninho por parabiose. Essa associação que ocorre em florestas tropicais ainda foi pouco estudada. O objetivo deste trabalho foi avaliar jardins de formigas na Amazônia Central determinando se as formigas identificam e removem potenciais herbívoros que estejam visitando as árvores hospedeiras de jardins de formigas ocupados pelas espécies Camponotus femoratus e Crematogaster levior. No estudo foram observadas 42 árvores contendo jardins de formigas. Em cada árvore foi colocado um cupim, como isca, a diferentes distâncias do ninho, contabilizado o tempo para sua remoção e observado se havia recrutamento de outras formigas para realizar a remoção da isca. Os resultados evidenciaram que ambas as espécies examinam as árvores hospedeiras para forragear. Durante a captura da isca, C. levior foi mais eficiente para detectar o cupim, não tendo sido observado recrutamento para carregá-lo ao ninho. Em alguns casos, indivíduos de C. femoratus identificaram a isca e indivíduos de C. levior a carregaram ao ninho. A relação entre árvore hospedeira e formigas beneficiam ambas, pois a árvore recebe proteção indireta contra cupins e fornece apoio para o ninho das formigas.(AU)
RESUMO
Ant gardens are a special association type between ants and epiphytes, in which two or more ant species can share the same nest in a parabiotic relationship. This association that occurs in tropical forests is still poorly understood. The aim of this study was to evaluate ants gardens in the Central Amazon and to determine if ants identify and remove potential herbivores that are visiting the host tree of ants gardens occupied by the species Camponotus femoratus and Crematogaster levior. In this study, it was observed 42 trees occupied by ants gardens. In each tree it was inserted a termite as bait at different distances from the nest, the time of the termites' removal was recorded and it was observed if there was the need of assistance from other ants to perform the removal of the bait. The results revealed that both species examined the tree host to forage. During the capture of the bait, C. levior was more efficient to detect the termite, and it was not observed the need of recruits to carry it to the nest. In some cases, individuals of de C. femoratus identified the bait and individuals of C. levior carried to the nest. The relationship between the host tree and ants is beneficial to both of them, since the tree receives indirect protection against termites and gives support to the ants nest.
Jardins de formigas são um tipo especial de associação entre formigas e epífitas, em que duas ou mais espécies de formigas podem compartilhar o mesmo ninho por parabiose. Essa associação que ocorre em florestas tropicais ainda foi pouco estudada. O objetivo deste trabalho foi avaliar jardins de formigas na Amazônia Central determinando se as formigas identificam e removem potenciais herbívoros que estejam visitando as árvores hospedeiras de jardins de formigas ocupados pelas espécies Camponotus femoratus e Crematogaster levior. No estudo foram observadas 42 árvores contendo jardins de formigas. Em cada árvore foi colocado um cupim, como isca, a diferentes distâncias do ninho, contabilizado o tempo para sua remoção e observado se havia recrutamento de outras formigas para realizar a remoção da isca. Os resultados evidenciaram que ambas as espécies examinam as árvores hospedeiras para forragear. Durante a captura da isca, C. levior foi mais eficiente para detectar o cupim, não tendo sido observado recrutamento para carregá-lo ao ninho. Em alguns casos, indivíduos de C. femoratus identificaram a isca e indivíduos de C. levior a carregaram ao ninho. A relação entre árvore hospedeira e formigas beneficiam ambas, pois a árvore recebe proteção indireta contra cupins e fornece apoio para o ninho das formigas.