Platelet microparticles contribute to aortic vascular endothelial injury in diabetes via the mTORC1 pathway

BackgroundGlomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction.MethodsWe studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry.ResultsPlasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle–derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury.ConclusionsThese findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.

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Hydroxyl Safflower Yellow Pigment A (HSYA) Improves Vascular Endothelial Injury Induced by Lipopolysaccharide In Vitro Study

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2596 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1792-1798

Author(s):

Li Yan ◽

Ge Jingping ◽

Yin Yuanyuan ◽

Li Xiaomei ◽

Zhao Boxiang ◽

...

Keyword(s):

Cell Proliferation ◽

In Vitro Study ◽

Treated Group ◽

Yellow Pigment ◽

Endothelial Injury ◽

Vitro Study ◽

Vascular Endothelial ◽

Treatment Groups ◽

Dose Dependent

Aim: This research was to investigate the effects and mechanisms of HSYA in vascular endothelial injury by vitro study. Methods: Dividing HUVECs as Normal Control (NC), Model (LPS treated) group, HSYA-L, HSYA-M and HSYA-H groups. Cells in the HSYA treatment groups were treated with LPS, followed by 40 mg/ml, 80 mg/ml, and 120 mg/ml HSYA intervention (HSYA-L, HSYA-M, and HSYA -H groups), respectively. Measuring the cell proliferation, apoptosis, relative proteins and mRNA (TLR4, MyD88 and NF-κB(p65)) expressions by MTT, Flow cytometry, WB and RT-qPCR assay. Using cellular immunofluorescence to evaluate NF-κB(p65) nuclear volume of difference groups. Results: With HSYA supplement, the cell proliferation rates were significantly up-regulation with cell apoptosis significantly down-regulation with TLR4 relatived mRNA and proteins and NF-κB(p65) nuclear significantly depressed with dose-dependent (P <0.05, respectively). Conclusion: HSYA improved vascular endothelial injury induced by LPS via TLR4 pathway In Vitro.

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Abstract 113: Regulation Of Aortic Vasodilation By Sigma-1 Receptor Stimulation In Ovariectomized And Pressure Overloaded Rats.

Circulation Research ◽

10.1161/res.113.suppl_1.a113 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Hideaki Tagashira ◽

Takayuki Matsumoto ◽

Kumiko Taguchi ◽

Tsuneo Kobayashi ◽

Kohji Fukunaga

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Pressure Overload ◽

Endothelial Injury ◽

Vascular Endothelial ◽

Aortic Banding ◽

Descending Aorta ◽

Sigma 1 Receptor ◽

Ovx Rats ◽

Sigma 1

Objective: We previously reported that sigma-1 receptor ( σ 1 R ) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ 1 R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. Methods: SA4503 (0.3-1.0 mg kg -1 ) and NE-100 (an σ 1 R antagonist, 1.0 mg kg -1 ) were administered orally for 4 weeks (once daily) to OVX-PO rats, starting from the onset of aortic banding. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. Results: σ 1 R expression in aortic smooth muscle and endothelial cells decreased significantly 4 weeks after PO in OVX rats (vs. Sham or OVX only group). SA4503 administration rescued PO-induced σ 1 R decreases in the descending aorta. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. Conclusions: σ 1 R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ 1 R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ 1 R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ 1 R to prevent vascular endothelial injury in postmenopausal woman.

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Impaired Autophagy Induced by oxLDL/β2GPI/anti-β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6662225 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Guiting Zhang ◽

Chao He ◽

Qianqian Wu ◽

Guoying Xu ◽

Ming Kuang ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Signaling Pathways ◽

Western Blotting ◽

Endothelial Injury ◽

Vascular Endothelial ◽

Endothelial Cell Dysfunction ◽

Western Blotting Analysis ◽

Cell Dysfunction ◽

Glycoprotein I

Endothelial cell dysfunction plays a fundamental role in the pathogenesis of atherosclerosis (AS), and endothelial autophagy has protective effects on the development of AS. Our previous study had shown that oxidized low-density lipoprotein/β2-glycoprotein I/anti-β2-glycoprotein I antibody (oxLDL/β2GPI/anti-β2GPI) complex could promote the expressions of inflammatory cytokines and enhance the adhesion of leukocytes to endothelial cells. In the present study, we aimed to assess the effects of oxLDL/β2GPI/anti-β2GPI complex on endothelial autophagy and explore the associated potential mechanisms. Human umbilical vein endothelial cells (HUVECs) and mouse brain endothelial cell line (bEnd.3) were used as models of the vascular endothelial cells. Autophagy was evaluated by examining the expressions of autophagic proteins using western blotting analysis, autophagosome accumulation using transmission electron microscopy, and RFP-GFP-LC3 adenoviral transfection and autophagic flux using lysosome inhibitor chloroquine. The expressions of phospho-PI3K, phospho-AKT, phospho-mTOR, and phospho-eNOS were determined by western blotting analysis. 3-Methyladenine (3-MA) and rapamycin were used to determine the role of autophagy in oxLDL/β2GPI/anti-β2GPI complex-induced endothelial cell dysfunction. We showed that oxLDL/β2GPI/anti-β2GPI complex suppressed the autophagy, evidenced by an increase in p62 protein, a decrease in LC3-II and Beclin1, and a reduction of autophagosome generation in endothelial cells. Moreover, inhibition of autophagy was associated with PI3K/AKT/mTOR and eNOS signaling pathways. Rapamycin attenuated oxLDL/β2GPI/anti-β2GPI complex-induced endothelial inflammation, oxidative stress, and apoptosis, whereas 3-MA alone induced the endothelial injury. Our results suggested that oxLDL/β2GPI/anti-β2GPI complex inhibited endothelial autophagy via PI3K/AKT/mTOR and eNOS signaling pathways and further contributed to endothelial cell dysfunction. Collectively, our findings provided a novel mechanism for vascular endothelial injury in AS patients with an antiphospholipid syndrome (APS) background.

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Verotoxin biology: molecular events in vascular endothelial injury

Kidney International ◽

10.1038/ki.2008.612 ◽

2009 ◽

Vol 75 ◽

pp. S17-S19 ◽

Cited By ~ 20

Author(s):

Tania N Petruzziello ◽

Imtiaz A Mawji ◽

Mukarram Khan ◽

Philip A Marsden

Keyword(s):

Endothelial Injury ◽

Vascular Endothelial ◽

Molecular Events

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Regulatory T Cells Limit Vascular Endothelial Injury and Prevent Pulmonary Hypertension

Circulation Research ◽

10.1161/circresaha.110.236927 ◽

2011 ◽

Vol 109 (8) ◽

pp. 867-879 ◽

Cited By ~ 151

Author(s):

Rasa Tamosiuniene ◽

Wen Tian ◽

Gundeep Dhillon ◽

Lijuan Wang ◽

Yon K. Sung ◽

...

Keyword(s):

T Cells ◽

Pulmonary Hypertension ◽

Regulatory T Cells ◽

Endothelial Injury ◽

Vascular Endothelial

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MiR-223-3p Alleviates Vascular Endothelial Injury by Targeting IL6ST in Kawasaki Disease

Frontiers in Pediatrics ◽

10.3389/fped.2019.00288 ◽

2019 ◽

Vol 7 ◽

Author(s):

Xiang Wang ◽

Yue yue Ding ◽

Ye Chen ◽

Qiu qin Xu ◽

Guang hui Qian ◽

...

Keyword(s):

Kawasaki Disease ◽

Endothelial Injury ◽

Vascular Endothelial

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The critical role of endothelial function in fine particulate matter-induced atherosclerosis

Particle and Fibre Toxicology ◽

10.1186/s12989-020-00391-x ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Shuang Liang ◽

Jingyi Zhang ◽

Ruihong Ning ◽

Zhou Du ◽

Jiangyan Liu ◽

...

Keyword(s):

Air Pollution ◽

Particulate Matter ◽

Vascular Function ◽

Fine Particulate Matter ◽

Critical Role ◽

Complex Mixture ◽

Endothelial Injury ◽

Vascular Endothelial ◽

Vasomotor Function ◽

Fine Particulate

AbstractAmbient and indoor air pollution contributes annually to approximately seven million premature deaths. Air pollution is a complex mixture of gaseous and particulate materials. In particular, fine particulate matter (PM2.5) plays a major mortality risk factor particularly on cardiovascular diseases through mechanisms of atherosclerosis, thrombosis and inflammation. A review on the PM2.5-induced atherosclerosis is needed to better understand the involved mechanisms. In this review, we summarized epidemiology and animal studies of PM2.5-induced atherosclerosis. Vascular endothelial injury is a critical early predictor of atherosclerosis. The evidence of mechanisms of PM2.5-induced atherosclerosis supports effects on vascular function. Thus, we summarized the main mechanisms of PM2.5-triggered vascular endothelial injury, which mainly involved three aspects, including vascular endothelial permeability, vasomotor function and vascular reparative capacity. Then we reviewed the relationship between PM2.5-induced endothelial injury and atherosclerosis. PM2.5-induced endothelial injury associated with inflammation, pro-coagulation and lipid deposition. Although the evidence of PM2.5-induced atherosclerosis is undergoing continual refinement, the mechanisms of PM2.5-triggered atherosclerosis are still limited, especially indoor PM2.5. Subsequent efforts of researchers are needed to improve the understanding of PM2.5 and atherosclerosis. Preventing or avoiding PM2.5-induced endothelial damage may greatly reduce the occurrence and development of atherosclerosis.

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