PT  - JOURNAL ARTICLE
AU  - Noelia Lozano-Vidal
AU  - Laura Stanicek
AU  - Diewertje I. Bink
AU  - Veerle Kremer
AU  - Alyson W. MacInnes
AU  - Stefanie Dimmeler
AU  - Reinier A. Boon
TI  - The PNUTS-PP1 axis regulates endothelial aging and barrier function via SEMA3B suppression
AID  - 10.1101/2020.08.10.243170
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.10.243170
4099  - http://biorxiv.org/content/early/2020/08/10/2020.08.10.243170.short
4100  - http://biorxiv.org/content/early/2020/08/10/2020.08.10.243170.full
AB  - Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determined the role of PNUTS in endothelial cell aging. We confirmed that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. To validate our findings in vivo, we generated an endothelial-specific inducible PNUTS-deficient mouse line (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice presented severe multiorgan failure and vascular leakage. We showed that the PNUTS binding motif for protein phosphatase 1 (PP1) is essential to maintain endothelial barrier function. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice revealed that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restored barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a PP1-SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs.Competing Interest StatementThe authors have declared no competing interest.