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Vascular Smooth Muscle Cell Senescence Promotes Atherosclerosis and Features of Plaque Vulnerability.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Wang, Julie 
Uryga, Anna K 
Reinhold, Johannes 
Figg, Nichola 
Baker, Lauren 

Abstract

BACKGROUND: Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown. METHODS AND RESULTS: We examined the expression of proteins that protect telomeres in VSMCs derived from human plaques and normal vessels. Plaque VSMCs showed reduced expression and telomere binding of telomeric repeat-binding factor-2 (TRF2), associated with increased DNA damage. TRF2 expression was regulated by p53-dependent degradation of the TRF2 protein. To examine the functional consequences of loss of TRF2, we expressed TRF2 or a TRF2 functional mutant (T188A) as either gain- or loss-of-function studies in vitro and in apolipoprotein E(-/-) mice. TRF2 overexpression bypassed senescence, reduced DNA damage, and accelerated DNA repair, whereas TRF2(188A) showed opposite effects. Transgenic mice expressing VSMC-specific TRF2(T188A) showed increased atherosclerosis and necrotic core formation in vivo, whereas VSMC-specific TRF2 increased the relative fibrous cap and decreased necrotic core areas. TRF2 protected against atherosclerosis independent of secretion of senescence-associated cytokines. CONCLUSIONS: We conclude that plaque VSMC senescence in atherosclerosis is associated with loss of TRF2. VSMC senes cence promotes both atherosclerosis and features of plaque vulnerability, identifying prevention of senescence as a potential target for intervention.

Description

Keywords

aging, atherosclerosis, muscle, smooth, vascular diseases, Animals, Atherosclerosis, Cells, Cultured, Cellular Senescence, Female, Humans, Male, Mice, Mice, Transgenic, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Plaque, Atherosclerotic

Journal Title

Circulation

Conference Name

Journal ISSN

0009-7322
1524-4539

Volume Title

132

Publisher

Ovid Technologies (Wolters Kluwer Health)
Sponsorship
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
Medical Research Council (G1000847)
Medical Research Council (G0800784)
British Heart Foundation (None)
British Heart Foundation (None)