Targeting QKI-7 in vivo restores endothelial cell function in diabetes

Abstract Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.

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Does the antihyperalgesic disruptor of endothelial cells, octoxynol-9, alter nociceptor function?

Journal of Neurophysiology ◽

10.1152/jn.00034.2014 ◽

2014 ◽

Vol 112 (2) ◽

pp. 463-466 ◽

Cited By ~ 2

Author(s):

Xiaojie Chen ◽

Paul G. Green ◽

Jon D. Levine

Keyword(s):

Endothelial Cell ◽

Mechanical Stimulation ◽

Cell Function ◽

Surface Active Agent ◽

Vascular Endothelial Cell ◽

Active Agent ◽

Endothelial Cell Function ◽

Endothelin 1 ◽

Mechanical Threshold

The vasoactive mediator, endothelin-1, elicits a novel form of hyperalgesia, stimulation-dependent hyperalgesia. Acting on its cognate receptor on the vascular endothelial cell, endothelin-1 produces a state in which mechanical stimulation now elicits release of pronociceptive mediators from endothelium that, in turn, acts at receptors on sensory neurons. The only evidence that octoxynol-9, a surface-active agent that attenuates both endothelial cell function and stimulus-dependent hyperalgesia, does not affect nociceptors is indirect (i.e., octoxynol-9 treatment did not affect behavioral nociceptive threshold or hyperalgesia induced by agents that act directly on nociceptors). To help address the question of whether the attenuation of stimulation-dependent hyperalgesia by octoxynol-9 treatment is due to alteration of nociceptor function, we used in vivo single-fiber electrophysiological recordings. Consistent with our previous behavioral observations, we observed no significant effect of octoxynol-9 on mechanical threshold in nociceptors, their response to sustained suprathreshold mechanical stimulation, conduction velocity, and change in mechanical threshold in response to the direct-acting hyperalgesic agent, PGE2. Although octoxynol-9 did not produce a biologically meaningful change in parameters of nociceptor function, we cannot exclude the possibility of a type II error. However, our data provide preliminary evidence of no effect of octoxynol-9 on nociceptors and are consistent with the suggestion that the primary action of octoxynol-9 in our studies is due to its action on the endothelium.

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The effect of novel magnetic nanoparticles on vascular endothelial cell function in vitro and in vivo

Journal of Hazardous Materials ◽

10.1016/j.jhazmat.2012.08.003 ◽

2012 ◽

Vol 235-236 ◽

pp. 316-325 ◽

Cited By ~ 12

Author(s):

Le Su ◽

Lei Han ◽

Fei Ge ◽

Shang Li Zhang ◽

Yun Zhang ◽

...

Keyword(s):

Endothelial Cell ◽

Magnetic Nanoparticles ◽

Cell Function ◽

Vascular Endothelial Cell ◽

Vascular Endothelial ◽

Endothelial Cell Function

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Enhanced Vascular Endothelial Cell Function on Nanostructured Titanium Surface Features: The Role of Nano to Submicron Roughness

MRS Proceedings ◽

10.1557/proc-1136-dd04-04 ◽

2008 ◽

Vol 1136 ◽

Cited By ~ 2

Author(s):

Jing Lu ◽

Dongwoo Khang ◽

Thomas J. Webster

Keyword(s):

Cell Adhesion ◽

Endothelial Cell ◽

Cell Function ◽

Vascular Endothelial Cell ◽

Vascular Endothelial ◽

Endothelial Cell Function ◽

Titanium Surfaces ◽

Endothelial Cell Adhesion

ABSTRACTTo study the contribution of different surface feature properties in improving vascular endothelial cell adhesion, rationally designed nano/sub-micron patterns with various dimensions were created on titanium surfaces in this study. In vitro results indicated that endothelial cell adhesion was improved when the titanium pattern dimensions decreased into the nano-scale. Specifically, endothelial cells preferred to adhere on sub-micron and nano rough titanium substrates compared to flat titanium. Moreover, titanium with nano and sub-micron roughness and with the same chemistry as compared to flat titanium, had significantly greater surface energy. Thus, the present study indicated the strong potential of surface nanotopography and nano/sub-micron roughness for improving current vascular stent design.

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THE MECHANISM OF BENEFICIAL EFFECTS OF ADRENOMEDULLIN (AM) AND ADRENOMEDULLIN BINDING PROTEIN-1 (AMBP-1) IN SEPSIS: MAINTENANCE OF VASCULAR ENDOTHELIAL CELL FUNCTION.

Shock ◽

10.1097/00024382-200206001-00156 ◽

2002 ◽

Vol 17 (Supplement) ◽

pp. 52 ◽

Cited By ~ 2

Author(s):

P. Wang ◽

D. E. Fowler ◽

S. Yang ◽

D. A. Ornan ◽

M. Zhou

Keyword(s):

Endothelial Cell ◽

Cell Function ◽

Binding Protein ◽

Vascular Endothelial Cell ◽

Vascular Endothelial ◽

Endothelial Cell Function ◽

Beneficial Effects

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Peroxynitrite increases iNOS through NF-κB and decreases prostacyclin synthase in endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00295.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. C395-C402 ◽

Cited By ~ 132

Author(s):

Christy-Lynn M. Cooke ◽

Sandra T. Davidge

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Vascular Reactivity ◽

Cell Function ◽

Vascular Endothelial Cell ◽

Vascular Endothelial ◽

Cell Nuclei ◽

Endothelial Cell Function ◽

Protein Mass ◽

Prostacyclin Synthase

Peroxynitrite, a marker of oxidative stress, is elevated in conditions associated with vascular endothelial cell dysfunction, such as atherosclerosis, preeclampsia, and diabetes. However, the effects of peroxynitrite on endothelial cell function are not clear. The endothelium-derived enzymes nitric oxide synthase (NOS) and prostaglandin H synthase (PGHS) mediate vascular reactivity and contain oxidant-sensitive isoforms (iNOS and PGHS-2) that can be induced by nuclear factor (NF)-κB activation. We investigated the effect(s) of peroxynitrite on NOS and PGHS pathways in endothelial cells. We hypothesized that peroxynitrite will increase levels of iNOS and PGHS-2 through activation of NF-κB. Western immunoblots of endothelial cells show that 3-morpholinosydnonimine (SIN-1; 0.5 mM), a peroxynitrite donor, increased iNOS protein mass, which can be inhibited by pyrroline dithiocarbamate (an NF-κB inhibitor) (167 ± 24.2 vs. 78 ± 19%, P < 0.05, n = 6). SIN-1 treatment also significantly increased NF-κB translocation into endothelial cell nuclei (135 ± 10%, P < 0.05). Endothelial NOS, PGHS-1, and PGHS-2 protein levels were not altered by SIN-1. However, prostacyclin synthase protein mass, but not mRNA, was significantly reduced in SIN-1-treated endothelial cells (78 ± 8.9%, P < 0.05). Our results illustrate novel mechanisms through which peroxynitrite may modulate vascular endothelial function.

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Vitamin D Promotes Vascular Endothelial Cell Function via the Regulation of miR-199a-5p

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2186 ◽

2019 ◽

Vol 9 (12) ◽

pp. 1662-1669

Author(s):

Lianman He ◽

Yong Wang ◽

Min Liu ◽

Ling Li

Keyword(s):

Vitamin D ◽

Endothelial Cell ◽

Cell Function ◽

Vascular Endothelial Cell ◽

Cell Counting ◽

Biological Behavior ◽

Luciferase Reporter ◽

Vascular Endothelial ◽

Endothelial Cell Function ◽

The Impact

Essential hypertension (EH) is a main risk factor for cardiovascular disease. Vitamin D (VD) levels are inversely related to hypertension. MicroRNAs (miRNA or miR) are involved in various diseases, including EH. Till now, the role of miR-199a-5p in EH remains unclear. Cell counting kit-8, flow cytometry and Transwell assay were carried out in the current study to study the effects of VD on the biological behavior of Human umbilical vein endothelial cells (HUVECs). The expression of miR-199a-5p was subsequently determined using reverse transcription-quantitative (RT-q) PCR. TargetScan prediction and double luciferase reporter gene detection were applied to confirm the binding sites between Sirtuin 1 (SIRT1) and miR-199a-5p. The results showed that VD promoted the proliferation and migration of HUVECs and reduced cell apoptosis. VD was observed to significantly reduced miR-199a-5p level in HUVECs. Transfection of the miR-199a-5p mimic was indicated to reverse the influence of VD on the proliferation, migration and apoptosis of HUVECs. SIRT1 was also confirmed to be a target gene of miR-199a-5p. Western blot analysis and RT-qPCR were performed to measure the impact of VD on the SIRT1/AMP-activated protein kinase (AMPK)- /NFB pathway. The results demonstrated that VD increased SIRT1 expression and p-AMPK- and decreased the expression of p-p65, and the transfection of miR-199a-5p mimic reversed these effects. In conclusion, the results of the current study indicated that VD may relieve EH through promoting vascular endothelial cell function via regulating miR-199a-5p.

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