Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function.

Autor:	Roy V; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Ross JP; McGill University, Montréal, Québec, Canada (J.P.R., D.E.P., P.A.D., G.A.R.)., Pépin R; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Cortez Ghio S; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Brodeur A; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Touzel Deschênes L; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Le-Bel G; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Phillips DE; McGill University, Montréal, Québec, Canada (J.P.R., D.E.P., P.A.D., G.A.R.)., Milot G; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Dion PA; McGill University, Montréal, Québec, Canada (J.P.R., D.E.P., P.A.D., G.A.R.)., Guérin S; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Germain L; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Berthod F; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Auger FA; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Rouleau GA; McGill University, Montréal, Québec, Canada (J.P.R., D.E.P., P.A.D., G.A.R.)., Dupré N; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.)., Gros-Louis F; CHU de Québec - Université Laval, Canada (V.R., R.P., S.C.G., A.B., L.T.D., G.L.-B., G.M., S.G., L.G., F.B., F.A.A., N.D., F.G.-L.).
Jazyk:	angličtina
Zdroj:	Stroke [Stroke] 2022 Apr; Vol. 53 (4), pp. 1263-1275. Date of Electronic Publication: 2022 Jan 07.
DOI:	10.1161/STROKEAHA.120.032691
Abstrakt:	Background: Variants in the ring finger protein 213 ( RNF213 ) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease. Methods: To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology. Results: In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines. Conclusions: Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu