ABSTRACT
ATP-binding cassette transporter A1 (ABCA1) plays an important role in the regulation of apolipoprotein E (ApoE) and the biogenesis of high-density lipoprotein (HDL) cholesterol in the mammalian brain. Cholesterol is a major source for myelination. Here, we investigate whether ABCA1/ApoE/HDL contribute to myelin repair and oligodendrogenesis in the ischemic brain after stroke. Specific brain ABCA1-deficient (ABCA1-B/-B) and ABCA1-floxed (ABCA1fl/fl) control mice were subjected to permanent distal middle-cerebral-artery occlusion (dMCAo) and were intracerebrally administered (1) artificial mouse cerebrospinal fluid (CSF) as vehicle control, (2) human plasma HDL3, and (3) recombined human ApoE2 starting 24 h after dMCAo for 14 days. All stroke mice were sacrificed 21 days after dMCAo. The ABCA1-B/-B-dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1fl/fl mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1-B/-B-dMCAo mice ( p < 0.05, n = 9/group). In vitro, ABCA1-B/-B reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1-B/-B-induced reduction in OPC migration and oligodendrocyte maturation. Our data indicate that the ABCA1/ApoE/HDL signaling pathway contributes to myelination and oligodendrogenesis in the ischemic brain after stroke.
Subject(s)
ATP Binding Cassette Transporter 1/genetics , Apolipoproteins E/administration & dosage , Lipoproteins, HDL3/administration & dosage , Myelin Sheath/metabolism , Oligodendroglia/cytology , Stroke/drug therapy , Animals , Apolipoproteins E/pharmacology , Cell Movement/drug effects , Cells, Cultured , Cerebrospinal Fluid/chemistry , Disease Models, Animal , Humans , Lipoproteins, HDL3/pharmacology , Male , Mice , Myelin Sheath/drug effects , Oligodendroglia/drug effects , Oligodendroglia/metabolism , Organogenesis/drug effects , Primary Cell Culture , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Signal Transduction , Stroke/etiology , Stroke/genetics , Stroke/metabolismABSTRACT
La aterotrombosis (aterosclerosis y sus complicaciones trombóticas) se caracteriza por el acúmulo de lípidos y células inflamatorias en la pared de vasos de mediano y gran calibre. Las lipoproteínas asociadas al colesterol juegan un papel central en la homeostasis de la placa de ateroma, siendo la lipoproteína de alta densidad (HDL) la responsable de la salida del colesterol y de su transporte al hígado para su ulterior excreción. El desarrollo de nuevas técnicas de imagen ha permitido documentar de forma longitudinal los cambios en el volumen de placa. Si bien no hay evidencia directa, datos indirectos confirman que la regresión del volumen de la placa puede asociarse a una disminución de episodios cardiovasculares. Por este motivo, la regresión de la placa/ausencia de progresión se utiliza como un objetivo subrogado con frecuencia creciente. De todas las terapias antiateroscleróticas testadas, el incremento de la HDL por diferentes abordajes es el que ha resultado más eficaz en regresar el volumen de placas de ateroma (AU)
Atherothrombosis (atherosclerosis and its thrombotic complications) is characterized by the accumulation of lipids and inflammatory cells in the walls of intermediate- and largecaliber vessels. The lipoproteins associated with cholesterol play a central role in homeostasis of the atheroma plaque while high-density lipoproteins (HDL) play a critical role in cholesterol efflux and cholesterol transport to the liver for subsequent excretion The development of new imaging techniques has allowed changes in plaque volume to be documented longitudinally. Although there is no direct evidence, indirect data confirm that regression of plaque volume can be associated with a reduction in cardiovascular events. For this reason, plaque regression/absence of progression is increasingly used as a surrogate objective. Of all the antiatherosclerotic therapies tested, the increase in HDL by distinct approaches is the most effective in reducing atheroma plaque volumen (AU)
