SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells

Abstract

Normal endothelial function relies on a balance between injuryand repair of endothelial cells. But regenerated endothelial cellsoften undergo senescence, initiating subsequent inflammatoryresponses. Senescent vascular endothelial cells are present inhuman atherosclerotic lesions. SIRT1 is a conserved deacetylasemediating lifespan extension and anti-aging effects in a variety ofspecies. However, its role in regulating endothelial senescence hasnot been well elucidated. In present study, we have found thatboth mRNA and protein levels of SIRT1 decrease during pro-longed culture of primary porcine aortic endothelial cells (PAE-Cs), which is a cellular model for endothelial replicative senes-cence established by our group. Exogenously added SIRT1 canprevent cellular senescence and recover the proliferative capacityof PAECs, while enhancing eNOS phosphorylation. Whenscreening the molecules that could interact with SIRT1, we haveidentified LKB1, a tumor suppressor, which dramaticallyincreases during the process of senescence. Our results haveproved that SIRT1 could deacetylate LKB1 and reduce its stabil-ity as well as protein levels. Over-expression of LKB1 in PAECsinduces endothelial senescence and retards the proliferation.These effects of LKB1 can be reversed by over-expression ofSIRT1. Similar result is not seen when using a mutant type ofSIRT1 that lacks deacetylase activity, suggesting that the effectsare deacetylation dependent. In summary, our results demon-strate that SIRT1 plays an important role in antagonizing senes-cence and maintaining normal endothelial functions, which atleast in part through targeting the functions of LKB1.