RESUMEN
The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic patients. It is also the most rapidly increasing risk factor for cognitive impairment, a silent disease that causes loss of creativity, productivity, and quality of life. Small vessel disease in the cerebral vasculature plays a major role in the pathogenesis of cognitive impairment in diabetes. Endothelin system, including endothelin-1 (ET-1) and the receptors (ET(A) and ET(B)), is a likely candidate that may be involved in many aspects of the diabetes cerebrovascular disease. In this review, we took a brain-centric approach and discussed the role of the ET system in cerebrovascular and cognitive dysfunction in diabetes.
Asunto(s)
Encéfalo/metabolismo , Complicaciones de la Diabetes/metabolismo , Endotelinas/metabolismo , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Animales , Encéfalo/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Complicaciones de la Diabetes/tratamiento farmacológico , Antagonistas de los Receptores de la Endotelina A/administración & dosificación , Antagonistas de los Receptores de la Endotelina A/metabolismo , Antagonistas de los Receptores de la Endotelina B/administración & dosificación , Antagonistas de los Receptores de la Endotelina B/metabolismo , Endotelinas/agonistas , Endotelinas/antagonistas & inhibidores , HumanosRESUMEN
Diabetes increases the risk and worsens the progression of cognitive impairment. The hippocampus is an important domain for learning and memory. We previously showed that endothelin-1 (ET-1) reduced diabetes-induced inflammation in hippocampal neurons, suggesting a neuroprotective effect. Given that neurons and endothelial cells within the neurovascular unit depend on each other for proper function, we investigated the effect of ET-1 on brain-derived neurotrophic factor (BDNF) synthesis, a key neurotrophin and prosurvival factor, in neuronal (HT22 hippocampal neurons) and brain microvascular endothelial (BMEC-5i) cells under normal and diabetes-mimicking (high glucose plus palmitate) conditions. Cells were treated with exogenous ET-1 or ET receptor antagonists including ET(B) receptor selective antagonist BQ788 (1 microM) or dual-receptor antagonist bosentan (10 microM). Mature (m)BDNF, proBDNF and caspase-3 levels were measured by Western blotting. Diabetic conditions reduced the prosurvival mBDNF/proBDNF ratio in both HT22 and BMEC-5i cells. Addition of exogenous ET-1 had no effect on the BDNF system in HT22 cells in diabetic conditions. Both HT22 and BMEC-5i cells had an increase in the mBDNF/proBDNF ratio when grown in diabetes-simulating conditions in the presence of endothelin receptor inhibition. These data suggest that blockade of ET-1 may provide neuroprotection to hippocampal cells through the modulation of the BDNF system.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Endoteliales/metabolismo , Endotelina-1/metabolismo , Glucosa/toxicidad , Neuronas/metabolismo , Palmitatos/toxicidad , Animales , Línea Celular Transformada , Células Endoteliales/efectos de los fármacos , Endotelina-1/antagonistas & inhibidores , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Neuronas/efectos de los fármacosRESUMEN
Over activation of the endothelin-1 (ET-1) system in disease states contributes to endothelial dysfunction. On the other hand, ET-1 promotes proliferation and survival of endothelial cells. Regulation of programmed cell death (PCD) pathways is critical for cell survival. Recently discovered necroptosis (regulated necrosis) is a pathological PCD mechanism mediated by the activation of toll like receptor 4 (TLR4), which also happens to stimulate ET-1 production in dendritic cells. To establish the effect of ET-1 on PCD and survival of human brain microvascular endothelial cells (BMVECs) under control and inflammatory conditions, BMVECs were treated with ET-1 (10 nM, 100 nM and 1 microM) or lipopolysaccharide (LPS, 100 ng/ml). ET receptors were blocked with bosentan (10 microM). Under normal growth conditions, exogenous ET-1 reduced BMVEC viability and migration at a relatively high concentration (1 microM). This was accompanied with activation of necroptosis and apoptosis marker genes. LPS decreased endogenous ET-1 secretion, increased ET(B) receptor expression and activated necroptosis. Even though ET-1 levels were low (less than 10 nM levels used under normal growth conditions), blocking of ET receptors with bosentan inhibited the necroptosis pathway and improved the cell migration ability of BMVECs, suggesting that under inflammatory conditions, ET-1 activates PCD pathways in BMVECs even at physiological levels.
Asunto(s)
Encéfalo/metabolismo , Células Endoteliales/metabolismo , Antagonistas de los Receptores de Endotelina/farmacología , Lipopolisacáridos/toxicidad , Microvasos/metabolismo , Receptores de Endotelina/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Encéfalo/efectos de los fármacos , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Humanos , Microvasos/efectos de los fármacos , Necrosis/inducido químicamente , Necrosis/metabolismoRESUMEN
This study is the first report to suggest a morphological phylogenetic framework for the seven varieties of Ficus deltoidea Jack (Ficus: Moraceae) from the Malay Peninsula of Malaysia. Several molecular-based classifications on the genus Ficus had been proposed, but neither had discussed the relationship between seven varieties of F. deltoidea to its allies nor within the varieties. The relationship between seven varieties of F. deltoidea is still debated due to the extreme morphological variabilities and ambiguous boundaries between taxa. Thus, the correct identification of these varieties is important as several morphological characters are variety-specific. To test the monophyly and further resolved the relationship in F. deltoidea, a morphological phylogenetic analysis was conducted based on herbarium specimens representing the seven varieties of F. deltoidea that were collected from the Malay Peninsula of Malaysia, by using related species of the genus Ficus; F. grossularioides, F. ischnopoda and F. oleifolia as the outgroups. Parsimony and neighbour-joining analyses indicated that F. deltoidea is monophyletic, in that the seven varieties of F. deltoidea nested into two clades; clade subspecies deltoidea (var. deltoidea, var. bilobata, var. angustifolia, var. kunstleri and var. trengganuensis) and clade subspecies motleyana (var. intermedia and var. motleyana).