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oai:repisalud.isciii.es:20.500.12105/238322024-11-28T16:53:27Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16958col_20.500.12105_16961col_20.500.12105_16967col_20.500.12105_16983col_20.500.12105_16972
Repisalud author Medina-Dols, Aina author Cañellas, Guillem author Capó, Toni author Solé, Montse author Mola-Caminal, Marina author Cullell, Natalia author Jaume, Marina author Nadal-Salas, Laura author Llinàs, Jaume author Gómez, Lluis author Tur Campos, Silvia author Jiménez Martínez, Carmen author Diaz Navarro, Rosa author Carrera, Caty author Muiño, Elena author Gallego-Fabrega, Cristina author Soriano-Tarraga, Carolina author Ruiz-Guerra, Laura author Pol-Fuster, Josep author Asensio, Víctor José author Muncunill Farreny, Josep author Fleischer, Aarne author Iglesias, Amanda author Giralt-Steinhauer, Eva author Lazcano, Uxue author Fernández-Pérez, Isabel author Jiménez-Balado, Joan author Gabriel-Salazar, Marina author Garcia-Gabilondo, Miguel author Lei, Ting author Torres-Aguila, Nuria-Paz author Cárcel-Márquez, Jara author Lladó, Jerònia author Olmos, Gabriel author Rosell, Anna author Montaner, Joan author Planas, Anna M author Rabionet, Raquel author Hernández-Guillamon, Mar author Jiménez-Conde, Jordi author Fernández-Cadenas, Israel author Vives-Bauza, Cristofol 2024-10-09T07:09:19Z 2024-10-09T07:09:19Z 2024-02-17 Medina-Dols A, Cañellas G, Capó T, Solé M, Mola-Caminal M, Cullell N, et al. Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis. Cell death Discov. 2024 Feb 17;10(1):85. 10.1038/s41420-024-01857-z10.1038/s41420-024-01857-z 2058-7716 Cell death discovery https://hdl.handle.net/20.500.13003/20203 38368420 https://hdl.handle.net/20.500.12105/23832 Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery. eng Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis research article