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

Abstract

P roliferation of vascular smooth muscle cells (VSMCs) is a central axiom of most models of atherosclerosis, promoting atherogenesis as a response to injury 1 or inflammation. 2 However, most heart attacks are caused by rupture of a "vulnerable" plaque with a thin VSMC-poor fibrous cap overlying a relatively large necrotic core. 3,4 Plaque repair requires VSMC proliferation and is thus beneficial at this stage. However, VSMCs from advanced human plaques show poor proliferation and premature senescence in culture 5 and in vivo 6 ; furthermore, fibrous cap VSMCs show extensive DNA damage, marked telomere shortening, and markers of senescence. 7 Although these findings suggest that VSMC senescence may be important in atherogenesis, its mechanisms and direct consequences are unproven. Clinical Perspective on p 1919Replicative cell senescence is mediated in part by telomeres, which shorten during replication and ultimately trigger a DNA damage response (DDR) and growth arrest. Telomeres are composed of tandem DNA repeats that are maintained in a compact T-loop structure by the shelterin complex of telomere-associated proteins, including TRF1, TRF2, POT1, TIN2, RAP1, and TPP1. Shelterin proteins restrict access to telomerase and exonucleases/ligases, thus avoiding inappropriate telomere elongation and shortening, respectively, and prevent exposure of chromosome ends that are recognized as double-stranded DNA breaks (DSBs). Although each of the shelterin proteins is important for telomere maintenance, telomeric repeat-binding factor-2 (TRF2) has a particularly critical role. TRF2 regulates replicative senescence in part by reducing telomere length at senescence 8,9 and can also stop the ataxia telangiectasia kinase (ATM) from initiating a DDR from functional telomeres. 10 Loss of TRF2 induces multiple features of senescence, including irreversible growth arrest, expression of senescence-associated β-galactosidase, and telomere dysfunction with chromosomal fusions.11-13 TRF2 can also regulate cell longevity in a telomere-independent manner by direct association with multiple DDR proteins, including ATM, Nijmegen breakage syndrome-1, and checkpoint kinase-2.14-16 ATM phosphorylates TRF2 after DNA 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 degradat...

Social stress shortens lifespan in mice

“…Atherosclerosis and cardiovascular disease are among the major aging‐associated conditions in humans, and psychosocial factors such as job strain, low SES, and depression have been associated with increased risk of cardiovascular diseases and decreased lifespan (Kaplan & Manuck, 1999; Marmot et al., 1991; Rosengren et al., 2004; Shively, Register & Clarkson, 2009). Chronic stress can precipitate plaque progression in APOE−/− mice, increased sympathetic nervous system activation, HPA axis‐stimulated angiogenesis prompting inflammation with macrophage infiltration, and intraplaque hemorrhage (Heidt et al., 2014; Najafi et al., 2013; Wang et al., 2015). Notably, clearing senescent cells using either genetic approaches or senolytic drug treatments limits the development of atherosclerosis in the Ldlr−/− (Childs et al., 2017) or the APOE−/− (Wang et al., 2015) mouse models, a mechanism which is consistent with the phenotype of the subordinate mice and suggests a possible senescence‐associated link between stress and atherosclerosis.…”

“…Chronic stress can precipitate plaque progression in APOE−/− mice, increased sympathetic nervous system activation, HPA axis‐stimulated angiogenesis prompting inflammation with macrophage infiltration, and intraplaque hemorrhage (Heidt et al., 2014; Najafi et al., 2013; Wang et al., 2015). Notably, clearing senescent cells using either genetic approaches or senolytic drug treatments limits the development of atherosclerosis in the Ldlr−/− (Childs et al., 2017) or the APOE−/− (Wang et al., 2015) mouse models, a mechanism which is consistent with the phenotype of the subordinate mice and suggests a possible senescence‐associated link between stress and atherosclerosis.…”

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…Moreover, inflammation impairs satellite cell regenerative function 243–245 . Of note, the emergence of senescence traits in vascular smooth muscle cells has been implicated in the initiation and progression of CVD, specifically atherosclerosis 246 , again suggesting that atherosclerosis and the resulting CVD is a syndrome of accelerated ageing.…”

Vascular Smooth Muscle Cells in Atherosclerosis

“…These properties generate a pro-inflammatory environment, further promoting migration of inflammatory cells. Indeed, experimental induction of VSMC senescence has been shown to promote both plaque progression and features of unstable plaques 90 .…”