Vascular smooth muscle cell senescence and age-related diseases: State of the art

Chen, Chi; Li, Dongjie; Jiang, Yu‐Jie; Tong, Jie; Fu, Hui; Wu, Yicheng; Shen, Fu‐Ming

doi:10.1016/j.bbadis.2018.08.015

Cited by 117 publications

(103 citation statements)

References 178 publications

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“…In summary, emerging evidence supports a role for epigenetics in VSMC senescence and aging and in particular, proposed functions for miRNAs [reviewed in (21)]. Importantly, we have identified a novel mechanism linking aberrant miRNA-145 expression to SV-SMC senescence in the setting of macrovascular complications of T2DM.…”

Section: Pharmacologicalsupporting

confidence: 56%

“…We proceeded to explore components of the DDR and confirmed that T2DM-SMC exhibited persistent senescence and DNA damage evidenced by aberrant cell nuclei, increased phosphorylation of H2AX and increased gene expression of ATM, ATR and p21. Whilst higher mRNA expression levels of IL-8 suggested a developing SASP, this was not corroborated by IL-6 or MCP-1 mRNA expression, or increased protein secretion suggesting that T2DM-SMC had become senescent without progressing to the secretory phenotype (20,21). It was therefore logical to explore whether inflicting DNA damage per se in ND-SMC could drive the acquisition of a native T2DM-SMC phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Role of microRNA-145 in DNA damage signalling and senescence in vascular smooth muscle cells of Type 2 diabetic patients

Hemmings

Riches-Suman

Bailey

et al. 2020

Preprint

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Increased cardiovascular morbidity and mortality in individuals with type 2 diabetes (T2DM) is a significant clinical problem. Despite advancements in achieving good glycaemic control, this patient population remains susceptible to macrovascular complications. We previously discovered that vascular smooth muscle cells (SMC) cultured from T2DM patients exhibit persistent phenotypic aberrancies distinct from those of individuals without a diagnosis of T2DM. Notably, persistently elevated expression levels of microRNA-145 co-exist with characteristics consistent with aging, DNA damage and senescence. We hypothesised that increased expression of microRNA-145 plays a functional role in DNA damage signalling and subsequent cellular senescence specifically in SMC cultured from the vasculature of T2DM patients. In this study, markers of DNA damage and senescence were unambiguously and permanently elevated in native T2DM versus non-diabetic (ND)-SMC. Exposure of ND cells to the DNA-damaging agent etoposide inflicted a senescent phenotype, increased expression of apical kinases of the DNA damage pathway and elevated expression levels of microRNA-145. Overexpression of microRNA-145 in ND-SMC revealed evidence of functional links between them; notably increased secretion of senescence-associated cytokines and chronic activation of stress-activated intracellular signalling pathways, particularly the mitogen-activated protein kinase, p38α. Exposure to conditioned media from microRNA-145 overexpressing cells resulted in chronic p38α signalling in naïve cells, evidencing a paracrine induction and reinforcement of cell senescence. We conclude that targeting of microRNA-145 may provide a route to novel interventions to eliminate DNA-damaged and senescent cells in the vasculature and to this end further detailed studies are warranted.

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Section: Pharmacologicalsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Role of microRNA-145 in DNA damage signalling and senescence in vascular smooth muscle cells of Type 2 diabetic patients

Hemmings

Riches-Suman

Bailey

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…It is known that LTL is affected by environmental factors or lifestyles including smoking, alcohol abuse, obesity, psychological stress, lack of exercise and others [3], while all these elements are also associated with increased risk of EH and other cardiovascular diseases [21,25]. Therefore, it is difficult to distinguish whether shorter LTL and EH are only a coincidence or causally related.…”

Section: Discussionmentioning

confidence: 99%

“…Hypertension is a common age-related disease that causes atherosclerosis, stroke, and chronic kidney disease, and associates closely with morbidity and mortality worldwide [19,20]. In up to 95% of patients with hypertension, exact driving-factors are unknown, so-called essential hypertension (EH) [21]. It is in general thought that genetic and environmental elements interact to result in EH, and in this pathogenic process, age-related changes may play a pivotal role [19,20,22].…”

Section: Ivyspringmentioning

confidence: 99%

Shorter Leukocyte Telomere Length coupled with lower expression of Telomerase Genes in patients with Essential Hypertension

Cheng¹,

Wang²,

Dai³

et al. 2020

Int. J. Med. Sci.

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Background: The essential hypertension (EH) pathophysiology remains poorly understood. Many studies indicate that reduced leukocyte telomere length (LTL) is involved in the EH pathogenesis, however, the direct analysis of arterial telomere length (ATL) from EH patients and normotensive individuals did not show a difference. To address these discrepant observations between LTL and ATL, we performed comprehensive analyses of LTL, telomerase gene expression and their genetic variants in healthy normotensive controls and EH patients. Methods: Sex-matched 206 EH patients and equal numbers of healthy controls were recruited. LTL, and the expression of two key telomerase components, telomerase reverse transcriptase (TERT) and internal RNA template (TERC) were determined using qPCR. Genetic variants of rs2736100 at the TERT and rs12696304 at the TERC loci were determined using TaqMan genotyping kits. Results: LTL was significantly shorter in EH patients than in their normotensive controls (0.96 ± 0.52 vs 1.19 ± 0.58, P = 0.001). Moreover, TERT and TERC expression in patients' leukocytes were substantially lower compare to that in healthy controls (TERT, 0.98 ± 0.98 vs 1.76 ± 1.75, P = 0.003; TERC, 1.26 ± 1.62 vs 4.69 ± 3.61, P < 0.001). However, there were no differences in the genetic variants of rs2736100 and rs12696304 between patient and control groups. Conclusions: EH patients have significantly shorter LTL, which may result from defective TERT and TERC expression in leukocytes. Collectively, lower telomerase expression contributes to shorter LTL observed in EH patients, and telomerase activators may be considered for EH therapy.

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“…In the cardiovascular system, the senescence of vascular smooth muscle cells (VSMCs) may be induced by different stimuli, such as angiotensin II (AngⅡ), oxidative stress, inflammation, and DNA damage. On the other hand, VSMC senescence may also results in the loss of arterial function, chronic vascular inflammation, mitochondrial dysfunction, and the development of age-related vascular disorders, such as atherosclerosis, abdominal aortic aneurysm (AAA), hypertension, and diabetes (Chi et al, 2019;Lacolley et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

Zheng

et al. 2019

Preprint

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Though dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Klf5, an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here we show that Klf5 downregulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of Ang II-induced AAA by facilitating ROS formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eIF5a transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with Mfn1. Accordingly, decreased expression of eIF5a elicited by Klf5 downregulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

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Vascular smooth muscle cell senescence and age-related diseases: State of the art

Cited by 117 publications

References 178 publications

Role of microRNA-145 in DNA damage signalling and senescence in vascular smooth muscle cells of Type 2 diabetic patients

Role of microRNA-145 in DNA damage signalling and senescence in vascular smooth muscle cells of Type 2 diabetic patients

Shorter Leukocyte Telomere Length coupled with lower expression of Telomerase Genes in patients with Essential Hypertension

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

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