Abstract P3133: Endothelial Nup93 Selectively Regulates The LaminB1 Isoform To Limit Features Of Cellular Senescence And Consequent Endothelial Dysfunction

Abstract

Recent translational studies have focused on the role of the nuclear pore complexes (NPCs) and its component nucleoporin proteins ( i.e. nucleoporin93 [Nup93]) as potential mediators of cardiovascular disease (CVD). The nuclear pore complex (NPC) is one of the largest structures found in the nuclear envelope, serving as the main transport conduit between the nucleus and cytoplasm. While historically perceived as static gateways with the sole purpose of nucleocytoplasmic exchange, recent investigations implicate nucleoporins in several transport-independent features ( e.g. nuclear lamin organization). Here, we show that endothelial loss of Nup93, a critical NPC protein, selectively reduces expression of the laminB1 isoform while enhancing γ-H2AX-Ser139 phosphorylation, both well-known markers for cellular senescence. Co-immunoprecipitation experiments in Nup93-enriched fractions indicate a preferential association with the LaminB1 isoform, when compared to Lamin A/C. Furthermore, endothelial depletion of Nup93 promotes inflammation, increases stress fiber formation, and enhances paracellular permeability - all features of cellular senescence and ensuing EC dysfunction. Collectively, our data demonstrate that a Nup93-LaminB1 interaction may be required to maintain adequate LaminB1 expression in ECs, where the age-associated decline in Nup93 levels may selectively reduce LaminB1 isoform levels to drive the consequent pathological features of endothelial senescence, a known contributor to vascular aging and CVD.