Aging and Atherosclerosis

Wang, Julie C.; Bennett, Martin R.

doi:10.1161/circresaha.111.261388

Cited by 720 publications

(372 citation statements)

References 189 publications

(196 reference statements)

Supporting

Mentioning

323

Contrasting

Unclassified

Order By: Relevance

“…The cotreatment of cells with either NAC or caffeine inhibited the effects of L5 on DDR pathway activation. TP53 stabilization is critical for relaying the DDR and for executing the senescence response (Wang & Bennett, 2012; Zhan et al., 2010). We found that the small interfering RNA‐mediated silencing of TP53 in HAECs efficiently blocked the L5‐induced increase in SA‐β‐Gal staining and cellular senescence (Figure 5c–e).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, traditional cardiovascular risk factors have been shown to induce premature cardiovascular senescence (Erusalimsky, 2009). In vascular cells, the senescence response is believed to promote atherogenesis via the release of pro‐inflammatory cytokines and decreased nitric oxide production (Wang & Bennett, 2012). In preclinical models, the genetic or pharmacologic blockade of the senescence response has been shown to slow the progression of atherosclerosis (Mercer, Gray, Figg, Kumar, & Bennett, 2012; Zhan, Suzuki, Aizawa, Miyagawa, & Nagai, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

et al. 2018

View full text Add to dashboard Cite

SummaryDysregulation of plasma lipids is associated with age‐related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low‐density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5‐treated but not L1‐treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high‐fat diet, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N‐acetyl‐cysteine (free‐radical scavenger) or caffeine (ATM blocker), as well as in lectin‐like oxidized LDL receptor‐1 (LOX‐1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free‐radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5‐induced endothelial senescence. In conclusion, L5 may promote mitochondrial free‐radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5‐induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Aging is associated with endothelial cell dysfunction, and endothelial cell dysfunction is thought to be critical for the development of various vascular diseases (Wang & Bennett, 2012). However, the entire picture of age‐related endothelial dysfunction still remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Aging of endothelial cells (ECs) alters their structure and/or function, and is a critical event resulting in deterioration of vascular integrity (Tian & Li, 2014). Indeed, vascular aging is an independent risk factor of cardiovascular diseases that impair vascular health (Lakatta & Levy, 2003) and is now recognized as a target for intervention to achieve a healthier old age (Wang & Bennett, 2012). For that reason, understanding of the significance of age‐associated changes in the vascular endothelium is essential for the development of a therapeutic strategy to maintain vascular integrity (Brunner et al ., 2005).…”

Section: Introductionmentioning

confidence: 99%

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

2016

View full text Add to dashboard Cite

SummaryVasohibin‐1 (VASH1) is an angiogenesis‐inhibiting factor synthesized by endothelial cells (ECs) and it also functions to increase stress tolerance of ECs, which function is critical for the maintenance of vascular integrity. Here, we examined whether the expression of VASH1 would be affected by aging. We passaged human umbilical vein endothelial cells (HUVECs) and observed that VASH1 was downregulated in old HUVECs. This decrease in VASH1 expression with aging was confirmed in mice. To explore the mechanism of this downregulation, we compared the expression of microRNAs between old and young HUVECs by performing microarray analysis. Among the top 20 microRNAs that were expressed at a higher level in old HUVECs, the third highest microRNA, namely miR‐22‐3p, had its binding site on the 3′ UTR of VASH1 mRNA. Experiments with microRNA mimic and anti‐miR revealed that miR‐22‐3p was involved at least in part in the downregulation of VASH1 in ECs during replicative senescence. We then clarified the significance of this defective expression of VASH1 in the vasculature. When a cuff was placed around the femoral arteries of wild‐type mice and VASH1‐null mice, neointimal formation was augmented in the VASH1‐null mice accompanied by an increase in adventitial angiogenesis, macrophage accumulation in the adventitia, and medial/neointimal proliferating cells. These results indicate that in replicative senescence, the downregulation of VASH1 expression in ECs was caused, at least in part, by the alteration of microRNA expression. Such downregulation of VASH1 might be involved in the acceleration of age‐associated vascular diseases.

show abstract

“…Recent work suggests senescent cell burden can be dramatically increased by chronological aging or in models of progeria (Lecka‐Czernik et al ., 1997; Baker et al ., 2004; Varela et al ., 2005), high‐fat feeding (Shi et al ., 2007), diabetes (Verzola et al ., 2008), tobacco exposure (Nyunoya et al ., 2006), or atherosclerosis (Wang & Bennett, 2012), and short‐term treatment with ‘senolytic’ drugs in chronologically aged or progeroid mice alleviates several aging‐related phenotypes (Zhu et al ., 2015a,b). However, effects of long‐term senescent cell clearance on vascular reactivity and structure with aging or chronic hypercholesterolemia remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

et al. 2016

View full text Add to dashboard Cite

SummaryWhile reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long‐term senolytic treatment is unknown. To determine whether long‐term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF + cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK‐ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT–PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

show abstract

Aging and Atherosclerosis

Cited by 720 publications

References 189 publications

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

Contact Info

Product

Resources

About