endothelial inflammation
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eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Darian Williams ◽  
Marwa Mahmoud ◽  
Renfa Liu ◽  
Aitor Andueza ◽  
Sandeep Kumar ◽  
...  

Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified Kallikrein-Related Peptidase 10 (Klk10, a secreted serine protease) as a flow-sensitive gene in mouse arterial endothelial cells, but its role in endothelial biology and atherosclerosis was unknown. Here, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo& mouse models and in vitro studies with cultured endothelial cells (ECs). Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated Klk10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced permeability dysfunction and inflammation in human artery ECs (HAECs), as determined by NFkB activation, expression of vascular cell adhesion molecule 1 (VCAM1) and intracellular adhesion molecule 1 (ICAM1), and monocyte adhesion. Further, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of Klk10-expressing plasmids inhibited atherosclerosis in Apoe-/- mice. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques. KLK10 is a flow-sensitive endothelial protein that serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.


2021 ◽  
Author(s):  
Desislava Kalinova ◽  
Valentina Reshkova ◽  
Tzvetelina Velikova ◽  
Ekaterina Ivanova-Todorova ◽  
Dobroslav Kyurkchiev ◽  
...  

2021 ◽  
Vol 50 (1) ◽  
pp. 540-540
Author(s):  
Samuel Sherratt ◽  
Peter Libby ◽  
Deepak Bhatt ◽  
Hazem Dawoud ◽  
Tadeusz Malinski ◽  
...  

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Xiao-Hong Chen ◽  
Yu Tan ◽  
ShuQin Yu ◽  
Lijun Lu ◽  
Youqing Deng

2021 ◽  
Vol 12 ◽  
Author(s):  
Ji Hu ◽  
Ru Chen ◽  
Jie An ◽  
Yilong Wang ◽  
Minglu Liang ◽  
...  

Endothelial cells are the fundamental components of blood vessels that regulate several physiological processes including immune responses, angiogenesis, and vascular tone. Endothelial dysfunction contributes to the development of various diseases such as acute lung injury, and endothelial inflammation is a vital part of endothelial dysfunction. Dauricine is an extract isolated from Menispermum dauricum DC, a traditional Chinese medical plant that can be used for pharyngitis. In this work, we found that IL-1β-induced overexpression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin was inhibited by dauricine in primary human umbilical vein endothelial cells (HUVECs). Correspondingly, adhesion of human acute monocytic leukemia cell line (THP-1) to HUVECs was decreased by dauricine. Further studies showed that dauricine inhibited the activation of nuclear factor-κB (NF-κB) pathway in HUVECs stimulated with IL-1β. In vivo, dauricine protected mice from lipopolysaccharide (LPS)-induced acute lung injury. In lung tissues, the activation of NF-κB pathway and the expression of its downstream genes (ICAM-1, VCAM-1, and E-selectin) were decreased by dauricine, consistent with what was found in vitro. In summary, we concluded that dauricine could alleviate endothelial inflammation by suppressing NF-κB pathway, which might serve as an effective candidate for diseases related with endothelial inflammation.


2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yong Li ◽  
Qi Zhang ◽  
Na Li ◽  
Liting Ding ◽  
Jinping Yi ◽  
...  

Endothelial inflammation is a crucial event in the initiation of atherosclerosis. Here, we identify Ataxin-10 protein as a novel negative modulator of endothelial activation by suppressing IRF-1 transcription activity. The protein level of Ataxin-10 is relatively higher in human vascular endothelial cells, which can be significantly suppressed by TNF-α in both HUVECs and HLMECs. Overexpression of Ataxin-10 markedly inhibited the mRNA expressions of VCAM-1 and several cytokines including MCP-1, CXCL-1, CCL-5, and TNF-α; thus, it can also suppress monocyte adhesion to endothelial cells. Accordingly, Ataxin-10 silencing promoted endothelial inflammation. However, Ataxin-10 did not affect the MAPK/NF-κB signaling pathway stimulated by TNF-α in HUVECs. Using the yeast two-hybrid assay, we found that Ataxin-10 can directly bind to interferon regulatory factor-1 (IRF-1). Upon TNF-α stimulation, Ataxin-10 promoted the cytoplasmic localization of IRF-1, which inhibited the transcription of VCAM-1. Moreover, knockdown of IRF-1 can eliminate the effect of Ataxin-10 on the expression of VCAM-1 in HUVECs induced by TNF-α. Taken together, these results indicate that Ataxin-10 inhibits endothelial cell activation and may serve as a promising therapeutic target for some vascular inflammatory-related diseases such as atherosclerosis.


2021 ◽  
Vol 118 (48) ◽  
pp. e2115158118
Author(s):  
Chuan-Rong Zhao ◽  
Fang-Fang Yang ◽  
Qinghua Cui ◽  
Dong Wang ◽  
Yiran Zhou ◽  
...  

Vascular endothelial cells are exposed to shear stresses with disturbed vs. laminar flow patterns, which lead to proinflammatory vs. antiinflammatory phenotypes, respectively. Effective treatment against endothelial inflammation and the consequent atherogenesis requires the identification of new therapeutic molecules and the development of drugs targeting these molecules. Using Connectivity Map, we have identified vitexin, a natural flavonoid, as a compound that evokes the gene-expression changes caused by pulsatile shear, which mimics laminar flow with a clear direction, vs. oscillatory shear (OS), which mimics disturbed flow without a clear direction. Treatment with vitexin suppressed the endothelial inflammation induced by OS or tumor necrosis factor-α. Administration of vitexin to mice subjected to carotid partial ligation blocked the disturbed flow-induced endothelial inflammation and neointimal formation. In hyperlipidemic mice, treatment with vitexin ameliorated atherosclerosis. Using SuperPred, we predicted that apurinic/apyrimidinic endonuclease1 (APEX1) may directly interact with vitexin, and we experimentally verified their physical interactions. OS induced APEX1 nuclear translocation, which was inhibited by vitexin. OS promoted the binding of acetyltransferase p300 to APEX1, leading to its acetylation and nuclear translocation. Functionally, knocking down APEX1 with siRNA reversed the OS-induced proinflammatory phenotype, suggesting that APEX1 promotes inflammation by orchestrating the NF-κB pathway. Animal experiments with the partial ligation model indicated that overexpression of APEX1 negated the action of vitexin against endothelial inflammation, and that endothelial-specific deletion of APEX1 ameliorated atherogenesis. We thus propose targeting APEX1 with vitexin as a potential therapeutic strategy to alleviate atherosclerosis.


2021 ◽  
Author(s):  
Xia Wang ◽  
Yinhua Wang ◽  
Guo Zhou ◽  
Yi Li ◽  
Huanhuan Huo ◽  
...  

Abstract Background Sepsis-associated acute kidney injury (S-AKI) is a frequent complication of critical patients and is associated with high morbidity and mortality. The glomerular endothelial cell injury is the main characteristics during S-AKI. Ca2+ influx is a key step in the establishment of endothelial injury. Transient receptor vanilloid subtype 4 (TRPV4) ion channels are permeable to Ca2+ and are widely expressed in endothelial cells. However, the role of TRPV4 on glomerular endothelial inflammation in S-AKI has remained elusive. Methods Mouse glomerular endothelial cells (MRGEC) were used to test the molecular mechanism of TRPV4 on LPS-induced glomerular endothelial inflammation. The cecal-ligation-and-puncture (CLP) model was established by ligation of cecum with 4-0 suture and punctured with a 21-gauge needle. Then 0.2mL faeces was extruded from the puncture site to trigger peritoneal inflammation. Results In the present study, we found that blocking TRPV4 diminishes LPS-induced cytosolic Ca2+-elevations, which are essential for glomerular endothelial inflammation and barrier function. Furthermore, TRPV4 regulated LPS-induced phosphorylation and translocation of NF-κB and IRF-3 in mouse glomerular endothelial cells (MRGEC). Clamping intracellular Ca2+ mimics the LPS-induce response seen in the absence of TRPV4. In vivo, pharmacological blockade or knock down of TRPV4 reduced the inflammatory response of glomerular endothelial cells, inhibited translocation of NF-κB and IRF-3, increased survival rate and improved renal function in CLP-induced sepsis but without altering renal cortical blood perfusion. Conclusions Taken together, these results suggested that inhibition of TRPV4 ameliorates glomerular endothelial inflammation, kidney dysfunction, and increased mortality via mediating Ca2+ overload and NF-κB/IRF-3 activation. These discoveries may provide novel pharmacological strategies for the treatment of glomerular endothelial dysfunction and kidney injury during endotoxemia, sepsis, and other inflammatory diseases.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4153-4153
Author(s):  
Christina Caruso ◽  
Meredith E. Fay ◽  
Sunita I. Park ◽  
Todd A. Sulchek ◽  
Michael D. Graham ◽  
...  

Abstract Background: Iron deficiency anemia (IDA), which affects individuals of all ages worldwide, is an often overlooked and undertreated component of chronic disease, despite data correlating its association with adverse outcomes in patients with cardiovascular disease (von Haehling, Nat Rev Cardiol, 2015). While red blood cells (RBCs) in IDA are known to be smaller and contain less hemoglobin than healthy RBCs, how RBC deformability is altered in IDA remains poorly understood; some ektacytometry studies have observed impaired deformability in iron deficient RBCs (idRBCs), while others described either unchanged or increased deformability (Brandão, Clin Hemorheol Microcirc, 2009). Here we ask: can single cell biophysical techniques definitively determine whether idRBCs are less deformable than healthy RBCs and how heterogenous that phenomena may be? Recent investigations into IDA's role in cardiovascular disease have generally focused on the myocardium and coronary vasculature, yet much regarding other physiologic implications remains unknown, including whether idRBCs cause microvascular obstruction or vasculopathy. To address such questions, we leveraged a suite of microvascular models we developed. Methods: We first coupled our microfluidic capillary model with μEXACT, our customized automated particle tracking program for hematologic cell-based assays, to collect high-throughput velocity tracking of single RBCs from a healthy control and 2 IDA patients (anemic for age, ferritin <10 ng/mL) to create a single cell deformability index (sDI) for each RBC (Fig 1). Next, whole blood samples collected in EDTA tubes from the control and IDA patients were perfused into both straight 100μm wide channels (mimicking large venules) and branching 30μm wide microfluidic devices (mimicking smaller venules) at a constant shear rate for 30 minutes to observe if any occlusions or obvious alterations in flow were observed (Fig 2). Finally, using the straight 100μm channel microfluidic devices, human umbilical vein endothelial cells (HUVECs) were cultured throughout each microchannel and RBCs from a healthy control and 3 IDA patients were perfused in parallel microchannels for 4 hours. The endothelialized models were then fixed, permeabilized, and immunostained with antibodies against VCAM-1 and E-selectin, known markers of endothelial inflammation. Mean fluorescence intensity was measured to quantify endothelial inflammation (Fig 3). Results: sDI distribution histograms were obtained for healthy and IDA patient RBCs. The mean sDIs for IDA patient RBCs were decreased in comparison to the healthy RBCs. Additionally, both IDA patient's RBCs lacked a subpopulation of highly deformable RBCs, likely reticulocytes, seen in the healthy RBCs (Fig 1C). There was no evidence of microchannel occlusion for the healthy control or IDA patient whole blood samples in either the straight 100μm microchannels or branching 30μm microfluidic devices (Fig 2D). Finally, in our endothelialized microfluidic model, endothelium exposed to IDA patient RBCs exhibited increased VCAM-1 and E-selectin expression over endothelium exposed to healthy RBCs (Fig 3B). Conclusions: By utilizing an array of microfluidic models we can develop a more comprehensive understanding of the role idRBCs play systemically on microvasculature. Our combined microfluidic and image analysis system demonstrated decreased deformability in idRBCs and can offer detection of subpopulation differences that cannot be fully characterized with bulk techniques such as ektacytometry. So far, our data demonstrates that while no microvascular occlusion occurs, idRBCs contribute to endothelial inflammation. Additionally, the observation that physical interactions between endothelial cells and idRBCs are sufficient to cause endothelial inflammation warrants further investigation, as generally idRBCs had not been viewed as pro-inflammatory. Ongoing studies will couple unique sDI distribution curves with the degree of endothelial inflammation, as well as elucidate how these changes are associated with the degree of IDA or clinical events such as the initiation of iron supplementation. Utilizing atomic force microscopy to better understand how the idRBC membrane impacts deformability and developing biophysical computer simulations to determine if increased idRBC-endothelium interactions are observed in silico are also planned. Figure 1 Figure 1. Disclosures Lam: Sanguina, Inc.: Current holder of individual stocks in a privately-held company.


Author(s):  
Qingtao Meng ◽  
Qin Lu ◽  
Zhipeng Zhang ◽  
Jiyi Liu ◽  
Yu Lou ◽  
...  

Abstract Nesfatin-1 is a neuropeptide produced in the hypothalamus. It is known that Nesfatin-1 is involved in food uptake, fat storage, and other metabolic regulation. We hypothesized that Nesfatin-1 may play a role in cardiovascular tissue. Free fatty acids (FFAs) are known to be the risk factor for cardiovascular diseases. FFAs mediated endothelial dysfunction is the critical mechanism of many cardiovascular disorders. The present study explores the protective effects of Nesfatin-1 on FFAs-induced endothelial inflammation and the underlying mechanism. We found that significantly increased lactate dehydrogenase (LDH) release and production of inflammatory factors were observed in FFAs treated human aortic endothelial cells (HAECs), accompanied by the enhanced attachment of U937 monocytes to HAECs and upregulated cell adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), which were dramatically reversed by the treatment with Nesfatin-1. In addition, the promoted level of nuclear regulator NF-κB p65 and transcriptional function of NF-κB in FFAs treated HAECs were greatly suppressed by HAECs. Growth Factor Independent 1 Transcriptional Repressor 1 (Gfi1), an important negative regulator of NF-κB activity, was significantly downregulated in HAECs by FFAs and was upregulated by Nesfatin-1. Lastly, the inhibitory effects of Nesfatin-1 against FFAs-induced NF-κB activation and adhesion of U937 monocytes to HAECs were abolished by the knockdown of Gfi1. In conclusion, our data reveal that Nesfatin-1 inhibited FFAs-induced endothelial inflammation mediated by the Gfi1/NF-κB signaling pathway.


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