Age-associated stresses induce an anti-inflammatory senescent phenotype in endothelial cells

Coleman, Paul R.; Chang, Garry H.; Hutas, Gabor; Grimshaw, Matthew J.; Vadas, Mathew A.; Gamble, Jennifer R.

doi:10.18632/aging.100622

Cited by 39 publications

(31 citation statements)

References 40 publications

(47 reference statements)

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“…Oxidative stress and other stress factors are known to induce anti-inflammatory senescent phenotype in endothelial cells accompanied by reduced expression of the cell adhesion molecules [89]. The cell cycle arrest and anti-inflammatory phenotype was mediated by p38 MAPK [89, 90].…”

Section: Discussionmentioning

confidence: 99%

Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

Zinovkin

Romaschenko

Galkin

et al. 2014

Aging

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Vascular aging is accompanied by increases in circulatory proinflammatory cytokines leading to inflammatory endothelial response implicated in early atherogenesis. To study the possible role of mitochondria-derived reactive oxygen species (ROS) in this phenomenon, we applied the effective mitochondria-targeted antioxidant SkQ1, the conjugate of plastoquinone with dodecyltriphenylphosphonium. Eight months treatment of (CBAxC57BL/6) F1 mice with SkQ1 did not prevent age-related elevation of the major proinflammatory cytokines TNF and IL-6 in serum, but completely abrogated the increase in adhesion molecule ICAM1 expression in aortas of 24-month-old animals. In endothelial cell culture, SkQ1 also attenuated TNF-induced increase in ICAM1, VCAM, and E-selectin expression and secretion of IL-6 and IL-8, and prevented neutrophil adhesion to the endothelial monolayer. Using specific inhibitors to transcription factor NF-κB and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-κB activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-κB activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit IκBα. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-κB pathway and corresponding age-related inflammatory activation of endothelium.

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Section: Discussionmentioning

confidence: 99%

Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

Zinovkin

Romaschenko

Galkin

et al. 2014

Aging

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“…However, the correlation between hypoxia and senescence is controversial. Coleman et al [34] demonstrated that severe hypoxic conditions (< 0.5% O 2 ) induced senescence in endothelial cells. In addition, hypoxia and the hypoxia-mimetic agent CoCl 2 can induce senescence by upregulating Bcl-2 in melanoma cells [35].…”

Section: Hypoxic Induction Of the Ink4a Gene Despite An Increase In Tmentioning

confidence: 99%

Hypoxic reprograming of H3K27me3 and H3K4me3 at theINK4Alocus

et al. 2016

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Activation of Raf reduces the repressive histone mark H3K27me3 at the INK4a locus by inducing the H3K27me3 demethylase JMJD3. During hypoxia, the catalyitc activity of JMJD3 is reduced due to the limited availability of O 2 as a substrate. In our study, we found that hypoxia prevented Raf-induced JMJD3 from demethylating H3K27me3 at the INK4a locus. Nonetheless, hypoxia did not prevent Raf signaling from inducing INK4a mRNA. Interestingly, we found that hypoxia strongly enhanced the active histone mark H3K4me3 at the INK4a locus by inhibiting the H3K4me3 demethylases JARID1A and JARID1B. Therefore, this study demonstrates that the O 2 concentration in the microenvironment differentially affects the repressive methylation on K27 and the activating methylation on K4 at the INK4a locus by inhibiting the H3K27me3 and H3K4me3 demethylases.

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“…Endothelial dysfunction is associated with the pathogenesis of common diseases. Oxidative stress, hypoxia, and flow disturbances are important factors that are related to endothelial dysfunction (Coleman et al 2013).…”

Section: Introductionmentioning

confidence: 99%

The role of Nrf2 in oxidative stress-induced endothelial injuries

Chen

et al. 2015

Journal of Endocrinology

270

216

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Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

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Age-associated stresses induce an anti-inflammatory senescent phenotype in endothelial cells

Cited by 39 publications

References 40 publications

Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium

Hypoxic reprograming of H3K27me3 and H3K4me3 at theINK4Alocus

The role of Nrf2 in oxidative stress-induced endothelial injuries

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