The role of vascular cell senescence in atherosclerosis: antisenescence as a novel therapeutic strategy for vascular aging.
Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence." It has been reported that many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. Recently, senescent vascular cells have been demonstrated in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Introduction of telomere malfunction has been shown to lead to vascular dysfunction that promotes atherogenesis, whereas telomere lengthening extends cell lifespan and protects against vascular dysfunction associated with senescence. Indeed, recent studies have demonstrated that telomere attrition occurs in the blood vessels and is associated with human atherosclerosis. More recent evidence suggests that telomere-independent mechanisms are implicated in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby, promotes vascular inflammation in vitro and in vivo. Although a causal link between vascular aging and vascular cell senescence remains elusive, a large body of data is consistent with cellular senescence contributing to age-associated vascular disorders. This review considers the clinical relevance of vascular cell senescence in vivo and discusses the potential of antisenescence therapy for human atherosclerosis.
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
Tohru
T
Minamino
Hideyuki
H
Miyauchi
Toshihiko
T
Yoshida
Kaoru
K
Tateno
Issei
I
Komuro
D001808:Blood Vessels / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D016615:Telomere / Q000502:physiology