title: Clonal senescence alters endothelial ICAM-1 function.
abstract: Little is known how age alters the dynamics and function of cell adhesion molecules, especially under inflammatory and stressful conditions. One membrane constituent, intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein of the immunoglobulin (Ig) superfamily that regulates key outside-->in and inside-->out signals associated with cell-to-cell interactions. If conditions such as age and inflammation change usual ICAM-1 action then important downstream effects ultimately perturb endothelial cell function. In this report, ICAM-1 accumulates in late passage endothelial cells when compared to early passage endothelial cells, yet ICAM-1 protein expression is attenuated when senescent cells are challenged by TNF-alpha (10ng/ml). Importantly, age alters ICAM-1 dynamic properties from directed to random receptor motion within the membrane. Single particle tracking reveals that the average ICAM-1 mobility is 44% less in late than early passage cells after its motion is stimulated by the Protein Kinase C (PKC) activator, phorbol myristate acetate (PMA). The mechanism for altered ICAM-1 mobility partly can be explained by a reduced rate of alpha-actinin linking with ICAM-1 in late passage Human Pulmonary Artery Endothelial Cells (HPAECs). Furthermore, tyrosine phosphorylation of alpha-actinin, a requirment for ICAM-1 clustering, is markedly reduced in senescent cells. These findings support a hypothesis that senescence results in changes of ICAM-1 activation and clustering, thus resulting in an age-dependent transmembrane signaling disorder. Therefore, further understanding of age-dependent disturbances of ICAM-1 regulation during inflammation can provide important clues as to appropriate targets for therapeutic interventions and prevention of vascular disorders in elderly at the level of the endothelial surface membrane.
authors.affiliation: Section of Geriatric Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ximing
authors.initials: X
authors.lastname: Zhou
authors.forename: Felipe
authors.initials: F
authors.lastname: Perez
authors.forename: Kai
authors.initials: K
authors.lastname: Han
authors.forename: Donald A
authors.initials: DA
authors.lastname: Jurivich
mesh_terms: D000185:Actinin / Q000378:metabolism; D000328:Adult; D000368:Aged; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000185:Actinin; D018799:Intercellular Adhesion Molecule-1; D014443:Tyrosine; D011493:Protein Kinase C