Cellular and molecular biology of aging endothelial cells

Donato, Anthony J.; Morgan, R. Garrett; Walker, Ashley E.; Lesniewski, Lisa A.

doi:10.1016/j.yjmcc.2015.01.021

Cited by 417 publications

(402 citation statements)

References 283 publications

(338 reference statements)

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“…However, accumulating evidence indicates that the level of eNOS expression cannot explain the reduced availability of NO from aged ECs. Alternatively, the activity of eNOS, availability of substrate/cofactor of eNOS, and/or inactivation of generated NO are now thought to be related to the age‐associated impairment of endothelial integrity (Donato et al ., 2015). …”

Section: Introductionmentioning

confidence: 99%

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

2016

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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.

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Section: Introductionmentioning

confidence: 99%

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

2016

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“…During endothelial dysfunction, these properties are lost and endothelial cells (ECs) promote vascular disease development. 1,2 Understanding the fundamental mechanisms governing endothelial phenotype switching offers novel approaches to prevent and alter the course of vascular disease. Epigenetic mechanisms conserve the cellular identity and give rise to developmental processes.…”

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confidence: 99%

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Fork

Hitzel

et al. 2015

ATVB

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Objective-Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. Approach and Results-To identify chromatin modifying enzymes in endothelial cells, histone demethylases were screened by microarray and polymerase chain reaction. The histone 3 lysine 4 demethylase JARID1B was identified as a highly expressed enzyme at the mRNA and protein levels. Knockdown of JARID1B by shRNA in human umbilical vein endothelial cells attenuated cell migration, angiogenic sprouting, and tube formation. Similarly, pharmacological inhibition and overexpression of a catalytic inactive JARID1B mutant reduced the angiogenic capacity of human umbilical vein endothelial cells. To identify the in vivo relevance of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C, induced HOXA5 expression in human umbilical vein endothelial cells. Consistently, chromatin immunoprecipitation revealed that JARID1B occupies and reduces the histone 3 lysine 4 methylation levels at the HOXA5 promoter, demonstrating a direct function of JARID1B in endothelial HOXA5 gene regulation. Conclusions-JARID1B, by suppressing HOXA5, maintains the endothelial angiogenic capacity in a demethylasedependent manner.

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“…NF-B protein complex is involved in several cellular responses to stimuli, such as free radicals, stress, and cytokines (Donato et al, 2015), associated with activation of adhesion molecules, chemokines, and cytokines (Valen et al, 2001). Exposure of cells to TNF-α causes phosphorylation of the NF-κB inhibitory protein, IκB, which mediates its translocation to the nucleus and regulates the expression of numerous genes and proteins involved in inflammation (Lawrence, 2009).…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory property of Parkia speciosa empty pod extract in human umbilical vein endothelial cells

Mustafa

Ugusman²,

Jalil³

et al. 2018

J App Pharm Sci

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Parkia speciosa Hassk, locally known as petai papan, is a common medicinal plant found in Southeast Asia. Its empty pods were reported to contain high concentrations of polyphenols, particularly quercetin. This study aimed to evaluate the anti-inflammatory properties of P. speciosa empty pod extract in human umbilical vein endothelial cells (HUVECs). The empty pods were extracted by sequential fractionation with absolute ethanol and ethyl acetate. HUVECs were divided into four groups. HUVECs were exposed to tumor necrosis factor-α (TNF-α, 10 ng/mL) in the presence (25 µg/mL) or absence of Parkia speciosa extract. Quercetin (125 µM) served as the positive control, while another group that was not exposed to TNF-α acted as the negative control. The protein expressions of the inflammatory mediators, which were NF-κB p65, iNOS, COX-2 and VCAM-1, were significantly decreased in the P. speciosa and quercetin groups exposed to TNF-α. P. speciosa extract and quercetin also significantly reduced intracellular reactive oxygen species and nitric oxide levels as well as inducible nitric oxide synthase (iNOS) activity caused by TNF-α in HUVECs. In conclusion, P. speciosa empty pod extract exhibited potential anti-inflammatory properties against TNF-α-induced inflammation, possibly by modulating the NF-κB p65 pathway. The effects were comparable to that of quercetin.

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Cellular and molecular biology of aging endothelial cells

Cited by 417 publications

References 283 publications

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

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

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Anti-inflammatory property of Parkia speciosa empty pod extract in human umbilical vein endothelial cells

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