Identification of novel target genes for the prevention of inflammatory monocytes adhesion to senescent endothelial cells

Abstract

The mechanism for enhanced atherosclerosis with increasing age remains controversial. This study addressed this issue at the cellular level, by searching for genes uniquely expressed in senescent endothelial cells and functionally involved in inflammatory leukocytes adhesion, a critical initiation step of atherogenesis. Senescent human umbilical vein endothelial cells prepared by continuous sub‐culturing in vitro showed higher binding affinity for monocytes (THP‐1 cells, human acute monocytic leukemia cell line) compared with young cells. Comparing gene expression profiles between young and senescent endothelial cells by the cDNA microarray method, CD44 was identified as one of the ‘senescence‐induced cell adhesion genes’ whose expression was up‐regulated in senescent cells and whose gene ontology annotation indicated their role in cell adhesion. The enhanced gene expression of CD44 in senescent endothelial cells was verified at the mRNA and protein levels. Adhesion of monocytes to senescent endothelial cells was significantly reduced when endothelial cells were pretreated with CD44 antibody or small interfering RNA, supporting the critical role of CD44 in the inflammatory event. CD44 and other ‘senescence‐induced cell adhesion genes’ identified in this study may provide the novel targets for the prevention of inflammatory leukocytes adhesion leading to the development atherosclerosis.