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(Circulation Research. 2001;89:793.)
© 2001 American Heart Association, Inc.

Cellular Biology

eNOS Activity Is Reduced in Senescent Human Endothelial Cells

Preservation by hTERT Immortalization

Hidetsugu Matsushita, Edwin Chang, Alexander J. Glassford, John P. Cooke, Choy-Pik Chiu, Philip S. Tsao

From the Division of Cardiovascular Medicine, Department of Medicine (H.M., A.J.G., J.P.C., P.S.T.), Stanford University School of Medicine, Stanford, Calif; and the Geron Corp (E.C., C-P.C.), Menlo Park, Calif.

Correspondence to Philip S. Tsao, PhD, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5246. E-mail ptsao{at}stanford.edu

Advanced age is associated with endothelial dysfunction and increased risk for atherosclerosis. However, the mechanisms for these observed effects are not clear. To clarify the association between aging and loss of endothelial function, young human aortic endothelial cells (HAECs), senescent HAECs transfected with control vector, and immortalized HAECs containing human telomerase reverse transcriptase (hTERT) were compared for expression of endothelial nitric oxide synthase (eNOS) and production of NO. To investigate a specific function modulated by endothelial NO, adhesion of monocytes under basal conditions as well as after exposure to TNF- was assessed. A decrease in eNOS mRNA, protein, and activity was observed in endothelial cells at senescence as compared with young HAEC; this effect was blunted in hTERT cells. In all cells, shear stress induced a greater increase in the expression of eNOS protein with the final result being higher levels in hTERT compared with senescent cells. Basal monocyte binding was significantly elevated on aged endothelial cells compared with parental and hTERT cells. Exposure of TNF- resulted in a 2-fold increase in monocyte adhesion in senescent cells, whereas this effect was reduced in cells transfected with hTERT. Prior exposure to fluid flow significantly reduced subsequent monocyte adhesion in all groups. These studies demonstrate that replicative aging results in decreased endothelial expression of eNOS accompanied by enhanced monocyte binding. Stable expression of hTERT results in endothelial cells with a younger phenotype with greater amount of eNOS and NO activity. Thus, telomerase transfection may have important functional consequences on endothelial cells.

Key Words: aging • telomerase • atherosclerosis • nitric oxide • shear stress

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