Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis

Abstract

Abstract-Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. (VSMCs), and intracellular and extracellular lipids. Plaque disruption results in acute myocardial infarction and stroke, whereas repeated rounds of subclinical rupture and repair also promote plaque growth. Although VSMC proliferation occurs in atherogenesis, most proliferating cells are macrophages, and VSMC mitotic rates are lower in advanced plaques than early lesions, even after plaque rupture, 1 suggesting that plaque VSMCs may exhibit senescence.Cellular senescence can be defined as cell cycle arrest accompanying the exhaustion of replicative potential. 2 Senescent cells display a characteristic morphology (vacuolated, flattened cells) and gene expression, including markers such as senescence-associated ␤-galactosidase (SA␤G). 3 Senescence may be triggered by 2 broadly different mechanisms. In most primary cells, the telomeres of chromosomes shorten at each cell division because of incomplete chromosomal replication. Replicative senescence may be induced at critical telomere lengths or structures, such as telomeric fusion or dicentrics or loss of telomere-bound factors. 4,5 Cells also undergo "stress-induced premature senescence" (SIPS), for example, in response to activated oncogenes (eg, Ha-Ras) and suboptimal culture conditions. 6 Although telomere loss occurs with replication, both premature senescence and telomere breaks may be induced by oxidative DNA damage. Reactive oxygen species (ROS), particularly superoxide anions, hydrogen peroxide, and hydroxyl radicals, can produce a large variety of DNA damage, including DNA strand breaks and DNA base modifications. ROS can accelerate telomere loss during replication in some cell types 7 but also induces premature senescence independently of telomere shortening. 8 Increased levels of ROS are Original

Microarray analysis of senescent vascular smooth muscle cells: A link to atherosclerosis and vascular calcification

“…Evidence for telomere shortening in VSMCs has been provided by Matthews et al (2006), who also showed that telomere shortening in VSMCs was closely associated with increasing severity of atherosclerosis.…”

“…This implies that senescent VSMCs may persist in vivo long enough to be of physiological significance in the pathogenesis of vascular disease. However, it has been reported that apoptosis is a feature of advanced atherosclerosis and this could promote telomere shortening (and thus senescence) by reducing the number VSMCs capable of replication (Matthews et al, 2006). Apoptosis in this instance is likely related to disease specific changes, such as an increase in oxidative stress, which is not normally observed during cell culture.…”

“…Many studies have investigated the potential role of cellular senescence in the development and progression of disease, including atherosclerosis (Burton, 2009, Erusalimsky, 2009). Senescence in endothelial progenitor cells (EPCs), vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) have all been implicated in the development and progression of atherosclerosis (Yang et al, 2008, Minamino et al, 2008, Matthews et al, 2006. However, the majority the of work on cellular senescence has been carried out on fibroblasts, with limited understanding of the phenotype of many other cell types, especially those linked to age-related pathology.…”

Proteomic analysis of oxidative modification in endothelial colony-forming cells treated by hydrogen peroxide

“…In vitro, accumulation of prelamin A can cause nuclear morphology defect, premature senescence and failure to repair DNA (39)(40)(41). In vascular diseases, accumulation of prelamin A accelerates senescence in atherosclerotic plaques by interfering with DNA damage repair and mitosis (42). Dysfunctions of vascular endothelial and smooth muscle cells were also shown to be related to prelamin A accumulation at the cellular and nuclear levels (39,43,44).…”

Cellular Genome in Pathogenesis of Basic Diseases in Humans (Atherosclerosis, Autoimmune Diseases, Cancer)

“…Было показано, что при атеросклерозе в гладко-мышечных клетках сосудистой стенки отмеча-ется значительное уменьшение длины теломер и снижение активности теломеразы по сравне-нию с данными даже в клетках из непоражен-ных участков того пациента. Одной из главных причин этих изменений, по-видимому, является негативной влияние реактивных кислородных субстанций на активность теломеразы в клетках, помимо их повреждающих ДНК эффектов [30].…”