The Identification of the novel gene SENEX and its role in Endothelial Cell Senescence and Survival

Abstract

The Identification of the novel gene SENEX and its role in Endothelial Cell Senescence and Survival Cellular senescence was originally described as a mechanism to inhibit the growth of mammalians cells after oncogenic activation, in response to damage or following stress. Senescence is a permanent halt in the cell cycle and causes major alterations in the genetic profile of the cell. Recent research has demonstrated a significant role for senescence in human pathologies, such as tumour development and cardiovascular disease. We describe here the identification of a novel gene, which we have called SENEX, that regulates stress induced premature senescence pathways in endothelial cells (EC) involving p16INK4a and Rb activation. Endogenous levels of SENEX remain unchanged during replicative senescence but are upregulated by H2O2 mediated stress. In contrast to that previously described for senescence in other cell types, the SENEX induced senescent EC are profoundly anti-inflammatory. The cells are resistant to TNFα induced adhesion of neutrophils and mononuclear cells and the surface expression of E-selectin and VCAM1 is decreased in SENEX induced senescent cells. SENEX is also essential for EC survival since depletion by siRNA causes apoptosis. Together, these findings expand our understanding of the role of senescence in the vasculature and identifies SENEX as a fulcrum for driving the resultant phenotype of the endothelium.