Hypoxia-induced endothelial dysfunction in apolipoprotein E-deficient mice; effects of infliximab and l-glutathione

Tuleta, Izabela; França, Carolina Nunes; Wenzel, Daniela; Fleischmann, Bernd K.; Nickenig, Georg; Werner, Nikos; Skowasch, Dirk

doi:10.1016/j.atherosclerosis.2014.08.021

Cited by 39 publications

(23 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compared with the rats in the hypoxia group, the ADR and NADR release of those exposed to acute cold environment were significantly increased, indicating that low temperature significantly altered the catecholamine system. The current results involving cold or hypoxia are consistent with those observed by other studies (27–30). Furthermore, the results in rats exposed to hypoxia combined with cold environment revealed that ADR and NADR concentrations were significantly increased compared with the control group.…”

Section: Discussionsupporting

confidence: 93%

Diazoxide protects rat vascular endothelial cells against hypoxia and cold-induced damage

Zhang¹,

Li³

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

The present study aimed to examine the effects of hypoxia and cold on vascular endothelial cells (VECs), as well as the protective ability of novel VECs-protective drugs against these injuries. A rat model simulating exposure to hypoxia and cold at high altitude environments was established. Based on these animal experiments, rat aortic VECs were established as injury models and exposed to hypoxia and/or adrenaline (ADR) in vitro. The results revealed that hypoxia significantly altered the levels of nitric oxide and vascular endothelial growth factor, while the cold temperature significantly increased the release of ADR and noradrenaline. Exposure to hypoxia combined with cold temperature significantly affected all these indices. In vitro experiments demonstrated that hypoxia, ADR (which was used to simulate cold in the animal experiments) and the combination of the two factors resulted in damage to the VECs and endothelial dysfunction. In addition, the results also showed that diazoxide, a highly selective mitoKATP opener, protected VECs against these injuries. In conclusion, hypoxia and cold temperature induced endothelial cell dysfunction and endocrine disorders, respectively. Improving endothelial function using diazoxide may be an effective therapeutic strategy in patients with altitude-associated disorders. However, the potential for clinical application requires further study.

show abstract

Section: Discussionsupporting

confidence: 93%

Diazoxide protects rat vascular endothelial cells against hypoxia and cold-induced damage

Zhang¹,

Li³

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…As an oxidative stress-related disease, atherosclerosis is substantially affected by glutathione status. For example, intraperitoneal injection of GSH to apolipoprotein E-deficient mice reversed impairment of endothelial function induced by hypoxia and reduced the size of atherosclerotic plaques [33]. Deficiency in the modifier subunit (GCLM) of glutamate-cysteine ligase (GCL) increased the rate of aortic lesion development in apolipoprotein E-deficient mice, which was reduced by overexpression of the catalytic subunit of GCL (GCLC) [6].…”

Section: Introductionmentioning

confidence: 99%

Quercetin affects glutathione levels and redox ratio in human aortic endothelial cells not through oxidation but formation and cellular export of quercetin-glutathione conjugates and upregulation of glutamate-cysteine ligase

Zhang

Choi

et al. 2016

Redox Biology

View full text Add to dashboard Cite

Endothelial dysfunction due to vascular inflammation and oxidative stress critically contributes to the etiology of atherosclerosis. The intracellular redox environment plays a key role in regulating endothelial cell function and is intimately linked to cellular thiol status, including and foremost glutathione (GSH). In the present study we investigated whether and how the dietary flavonoid, quercetin, affects GSH status of human aortic endothelial cells (HAEC) and their response to oxidative stress. We found that treating cells with buthionine sulfoximine to deplete cellular GSH levels significantly reduced the capacity of quercetin to inhibit lipopolysaccharide (LPS)-induced oxidant production. Furthermore, incubation of HAEC with quercetin caused a transient decrease and then full recovery of cellular GSH concentrations. The initial decline in GSH was not accompanied by a corresponding increase in glutathione disulfide (GSSG). To the contrary, GSSG levels, which were less than 0.5% of GSH levels at baseline (0.26±0.01 vs. 64.7±1.9 nmol/mg protein, respectively), decreased by about 25% during incubation with quercetin. As a result, the GSH: GSSG ratio increased by about 70%, from 253±7 to 372±23. These quercetin-induced changes in GSH and GSSG levels were not affected by treating HAEC with 500 µM ascorbic acid phosphate for 24 h to increase intracellular ascorbate levels. Incubation of HAEC with quercetin also led to the appearance of extracellular quercetin-glutathione conjugates, which was paralleled by upregulation of the multidrug resistance protein 1 (MRP1). Furthermore, quercetin slightly but significantly increased mRNA and protein levels of glutamate-cysteine ligase (GCL) catalytic and modifier subunits. Taken together, our results suggest that quercetin causes loss of GSH in HAEC, not because of oxidation but due to formation and cellular export of quercetin-glutathione conjugates. Induction by quercetin of GCL subsequently restores GSH levels, thereby suppressing LPS-induced oxidant production.

show abstract

“…[5][6][7] Furthermore, evidence of endothelial dysfunction, an early event preceding the clinical manifestations of cardiovascular disease, is apparent in patients with OSA. [8][9][10] In animal models of OSA, intermittent hypoxic exposures as well as long-term sleep fragmentation induce endothelial dysfunction, 11,12 thereby indicating a potential causal relationship between OSA and the disrupted structural and functional integrity of the vasculature. In previous studies, we have exposed young healthy adults to intermittent hypoxia (IH), a potential major factor contributing to the pathogenesis of OSA-related comorbidities, and clearly demonstrated the presence of perturbations in endothelial function that are reversible upon termination of the IH exposures.…”

Section: Introductionmentioning

confidence: 99%

Effect on Intermittent Hypoxia on Plasma Exosomal Micro RNA Signature and Endothelial Function in Healthy Adults

Khalyfa

Zhang

Khalyfa

et al. 2016

Sleep

View full text Add to dashboard Cite

Study Objective: Intermittent hypoxia (IH) is associated with increased risk of cardiovascular disease. Exosomes are secreted by most cell types and released in biological fluids, including plasma, and play a role in modifying the functional phenotype of target cells. Using an experimental human model of IH, we investigated potential exosome-derived biomarkers of IH-induced vascular dysfunction. Methods: Ten male volunteers were exposed to room air (D0), IH (6 h/day) for 4 days (D4) and allowed to recover for 4 days (D8). Circulating plasma exosomes were isolated and incubated with human endothelial monolayer cultures for impedance measurements and RNA extracted and processed with messenger RNA (mRNA) arrays to identify gene targets. In addition, immunofluorescent assessments of endothelial nitric oxide synthase (eNOS) mRNA expression, ICAM-1 cellular distribution were conducted. Results: Plasma exosomal micro RNAs (miRNAs) were profiled. D4 exosomes, primarily from endothelial sources, disrupted impedance levels compared to D0 and D8. ICAM-1 expression was markedly upregulated in endothelial cells exposed to D4 exosomes along with significant reductions in eNOS expression. Microarray approaches identified a restricted and further validated signature of exosomal miRNAs in D4 exosomes, and mRNA arrays revealed putative endothelial gene target pathways. Conclusions:In humans, intermittent hypoxia alters exosome cargo in the circulation which promotes increased permeability and dysfunction of endothelial cells in vitro. A select number of circulating exosomal miRNAs may play important roles in the cardiovascular dysfunction associated with OSA by targeting specific effector pathways.

show abstract

Hypoxia-induced endothelial dysfunction in apolipoprotein E-deficient mice; effects of infliximab and l-glutathione

Cited by 39 publications

References 39 publications

Diazoxide protects rat vascular endothelial cells against hypoxia and cold-induced damage

Diazoxide protects rat vascular endothelial cells against hypoxia and cold-induced damage

Quercetin affects glutathione levels and redox ratio in human aortic endothelial cells not through oxidation but formation and cellular export of quercetin-glutathione conjugates and upregulation of glutamate-cysteine ligase

Effect on Intermittent Hypoxia on Plasma Exosomal Micro RNA Signature and Endothelial Function in Healthy Adults

Contact Info

Product

Resources

About