scholarly journals Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells

Perfusion ◽  
2021 ◽  
pp. 026765912110125
Author(s):  
Alexander O Ward ◽  
Graciela B Sala-Newby ◽  
Shameem Ladak ◽  
Gianni D Angelini ◽  
Massimo Caputo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Vascular Endothelial Cell ◽  
High Shear ◽  
High Shear Stress ◽  
Protective Environment ◽  
The Impact

Vascular endothelial cell stimulation is associated with the activation of different signalling pathways and transcription factors. Acute shear stress is known to induce different pro-inflammatory mediators such as IL-8. Nrf2 is activated by prolonged high shear stress promoting an antiinflammatory and athero-protective environment. However, little is known about the impact of acute shear stress on Nrf2 and Keap1 function and its role in IL-8 regulation. We aimed to examine Nrf2-Keap1 complex activation in-vitro and its role in regulating IL-8 transcripts under acute arterial shear stress (12 dyn/cm2) in venous endothelial cells (ECs). We note that acute high shear stress caused a significant upregulation of Nrf2 target genes, HO-1 and GCLM and an increased IL-8 upregulation at 90 and 120 minutes. Mechanistically, acute high shear did not affect Nrf2 nuclear translocation but resulted in reduced nuclear Keap1, suggesting that the reduction in nuclear Keap1 may result in increased free nuclear nrf2 to induce transcription. Consistently, the suppression of Keap1 using shRNA (shKeap1) resulted in significant upregulation of IL-8 transcripts in response to acute shear stress. Interestingly; the over expression of Nrf2 using Nrf2-Ad-WT or Sulforaphane was also associated with significant upregulation of IL-8 compared to controls. This study highlights the role of Keap1 in Nrf2 activation under shear stress and indicates that activation of Nrf2 may be deleterious in ECs in the context of acute haemodynamic injury.

scholarly journals Nitric Oxide–Dependent and Nitric Oxide–Independent Transcriptional Responses to High Shear Stress in Endothelial Cells

Hypertension ◽  
2005 ◽  
Vol 45 (4) ◽  
pp. 672-680 ◽  
Author(s):  
Branko Braam ◽  
Remmert de Roos ◽  
Hans Bluyssen ◽  
Patrick Kemmeren ◽  
Frank Holstege ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
High Shear ◽  
High Shear Stress ◽  
Transcriptional Responses

scholarly journals Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

2020 ◽  
pp. 1902061
Author(s):  
David Macias ◽  
Stephen Moore ◽  
Alexi Crosby ◽  
Mark Southwood ◽  
Xinlin Du ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

Platelets, after Exposure to a High Shear Stress, Induce IL-10-Producing, Mature Dendritic Cells In Vitro

2004 ◽  
Vol 172 (9) ◽  
pp. 5297-5303 ◽  
Author(s):  
Masao Hagihara ◽  
Ayako Higuchi ◽  
Noriko Tamura ◽  
Yoko Ueda ◽  
Kaori Hirabayashi ◽  
...  
Keyword(s):  
Shear Stress ◽  
Dendritic Cells ◽  
High Shear ◽  
High Shear Stress

Shear Stress Initiates Cyclophilin D-Dependent Phosphatidylserine Exposure and Integrin αIIbβ3 Cleavage in Platelets

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3301-3301
Author(s):  
Fang Liu ◽  
Shawn M Jobe
Keyword(s):  
Shear Stress ◽  
Extracellular Calcium ◽  
Stress Conditions ◽  
High Shear ◽  
Cyclophilin D ◽  
High Shear Stress ◽  
Integrin Αiibβ3 ◽  
Platelet Accumulation ◽  
Platelet Formation

Abstract Abstract 3301 When platelets are simultaneously stimulated by multiple agonists, such as thrombin and collagen, a subpopulation of procoagulant platelets is formed that is characterized by phosphatidylserine (PS) exposure, integrin αIIbβ3 inactivation, and a rounded morphology in a process that is dependent on the mitochondrial permeability transition pore (mPTP) regulatory protein cyclophilin D (CypD). Recently, we have found that, in the absence of platelet CypD, platelet accumulation is markedly accentuated both in vitro and in vivo indicating that CypD-dependent procoagulant platelet formation may limit thrombus growth. Interestingly, the importance of CypD in limiting platelet accumulation was most evident in shear stress conditions consistent with arterial flow. In low (300 s−1) and high (1500 s−1) shear conditions, CypD null platelet accumulation was increased 1.5- and 4-fold compared to wild type platelets, respectively. Platelet activation and procoagulant platelet formation were examined in various shear conditions. In platelets subjected to increasing shear, PS exposure, but not P-selectin expression or integrin αIIbβ3 activation, was observed in a platelet subpopulation. When subjected to high shear in vitro as many as 70 % of platelets expressed high levels of PS on their surface within 5 min, and shear-dependent PS exposure was observed in as little as 30 seconds in high shear stress conditions. Previously we demonstrated that agonist-initiated PS exposure is closely associated with integrin αIIbβ3 cleavage and inactivation. In shear-treated, as in strongly-stimulated platelets, integrin αIIbβ3 cleavage was closely associated with PS exposure. PS exposure and integrin αIIbβ3 cleavage were not observed in the absence of VWF. In contrast to agonist-initiated PS exposure, shear stress-induced PS exposure was observed even in the absence of extracellular calcium. In a previous study, platelet PS exposure and apoptosis induced by ristocetin were found to be closely associated with an increase in the expression of the BH3-proteins, Bax and Bak. This finding, along with the observation that shear-stress dependent PS exposure occurred even in the absence of extracellular calcium led us to examine the role of Bax and Bak. However, shear stress-induced PS exposure was unaffected in Bax/Bak null platelets. In contrast, both shear stress-induced PS exposure and integrin αIIbβ3 cleavage were markedly blunted in CypD null platelets. Furthermore, shear stress induced-PS exposure was closely associated with loss of mitochondrial transmembrane potential, together indicating the importance of mPTP formation in the regulation of PS exposure in high shear stress conditions. These data identify a novel VWF- and CypD-dependent pathway that results in rapid PS exposure and integrin αIIbβ3 cleavage in high-shear stress conditions. This shear stress-initiated pathway of PS exposure, distinct from thrombin-collagen initiated PS exposure, does not require extracellular calcium and is not associated with P-selectin expression. Disclosures: Jobe: Baxter: Membership on an entity's Board of Directors or advisory committees.

Effects of high shear stress on morphology and MMP production of vascular endothelial cells

2017 ◽  
Vol 2017 (0) ◽  
pp. S0210101
Author(s):  
Yuta HORIE ◽  
Yuki OYAMA ◽  
Kouhei TATEBAYASHI ◽  
Masanori NAKAMURA ◽  
Naoya SAKAMOTO
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
High Shear ◽  
High Shear Stress

Absolute hypoxic exercise training enhances in vitro thrombin generation by increasing procoagulant platelet-derived microparticles under high shear stress in sedentary men

2013 ◽  
Vol 124 (10) ◽  
pp. 639-649 ◽  
Author(s):  
Yu-Wen Chen ◽  
Yi-Ching Chen ◽  
Jong-Shyan Wang
Keyword(s):  
Shear Stress ◽  
Exercise Training ◽  
Thrombin Generation ◽  
Coagulation Factor ◽  
Strenuous Exercise ◽  
Factor V ◽  
High Shear ◽  
High Shear Stress ◽  
Vigorous Exercise

HS (high shear) stress associated with artery stenosis facilitates TG (thrombin generation) by increasing the release of procoagulant PDMPs (platelet-derived microparticles). Physical exercise and hypoxia may paradoxically modulate vascular thrombotic risks. The aim of the present study was to investigate how exercise training with/without hypoxia affected TG mediated by PDMPs under physio-pathological shear flows. A total of 75 sedentary males were randomly divided into five groups (n=15 in each group): 21% O2 [NC (normoxic control)] or 15% O2 [HC (hypoxic control)] at rest or were trained at 50% of peak work rate under 21% O2 [NT (normoxic training)] or 15% O2 [HAT (hypoxic-absolute training)], or 50% of HR (heart rate) reserve under 15% O2 [HRT (hypoxic-relative training)] for 30 min/day, 5 days/week for 4 weeks. The PDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography respectively. Before the intervention, strenuous exercise markedly increased the PDMP count (14.8%) and TG rate (19.5%) in PDMP-rich plasma at 100 dynes/cm2 of shear stress (P<0.05). After the interventions, both NT and HRT significantly attenuated the enhancement of HS-induced PDMPs (4.7 and 4.9%) and TG rate (3.8 and 3.0%) (P<0.05) by severe exercise. Conversely, HAT notably promoted the PDMP count (37.3%) and TG rate (38.9%) induced by HS (P<0.05), concurrent with increasing plasma TF (tissue factor) and coagulation factor V levels at rest or following exercise. We conclude that both HRT and NT depress similarly HS-mediated TG during exercise, but HAT accelerates the prothrombotic response to vigorous exercise. These findings provide new insights into how exercise training under a hypoxic condition influences the risk of thrombosis associated with stenotic arteries.

scholarly journals Dehydroepiandrosterone Stimulates Endothelial Proliferation and Angiogenesis through Extracellular Signal-Regulated Kinase 1/2-Mediated Mechanisms

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 889-898 ◽  
Author(s):  
Dongmin Liu ◽  
Mary Iruthayanathan ◽  
Laurie L. Homan ◽  
Yiqiang Wang ◽  
Lingling Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Vascular Function ◽  
Nuclear Translocation ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Vascular Effect ◽  
Endothelial Proliferation ◽  
Ribosomal S6 Kinase

Dehydroepiandrosterone (DHEA) activates a plasma membrane receptor on vascular endothelial cells and phosphorylates ERK 1/2. We hypothesize that ERK1/2-dependent vascular endothelial proliferation underlies part of the beneficial vascular effect of DHEA. DHEA (0.1–10 nm) activated ERK1/2 in bovine aortic endothelial cells (BAECs) by 15 min, causing nuclear translocation of phosphorylated ERK1/2 and phosphorylation of nuclear p90 ribosomal S6 kinase. ERK1/2 phosphorylation was dependent on plasma membrane-initiated activation of Gi/o proteins and the upstream MAPK kinase because the effect was seen with albumin-conjugated DHEA and was blocked by pertussis toxin or PD098059. A 15-min incubation of BAECs with 1 nm DHEA (or albumin-conjugated DHEA) increased endothelial proliferation by 30% at 24 h. This effect was not altered by inhibition of estrogen or androgen receptors or nitric oxide production. There was a similar effect of DHEA to increase endothelial migration. DHEA also increased the formation of primitive capillary tubes of BAECs in vitro in solubilized basement membrane. These rapid DHEA-induced effects were reversed by the inhibition of either Gi/o-proteins or ERK1/2. Additionally, DHEA enhanced angiogenesis in vivo in a chick embryo chorioallantoic membrane assay. These findings indicate that exposure to DHEA, at concentrations found in human blood, causes vascular endothelial proliferation by a plasma membrane-initiated activity that is Gi/o and ERK1/2 dependent. These data, along with previous findings, define an important vascular endothelial cell signaling pathway that is activated by DHEA and suggest that this steroid may play a role in vascular function.

Albumin Uptake Into Endothelial Cells in Separated Flow

2000 ◽  
Author(s):  
Susumu Kudo ◽  
Ryuhei Yamaguchi ◽  
Masashi Sato ◽  
Kotaro Oka ◽  
Kazuo Tanishita
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Cell Morphology ◽  
Stress Gradient ◽  
Separated Flow ◽  
High Shear ◽  
High Shear Stress ◽  
Low Shear Stress ◽  
Shear Stress Gradient ◽  
Low Shear

Abstract The purpose of this study is to reveal the albumin uptake into endothelial cells in the separated flow area. After 24 hr of exposure to flow induced in a back step flow channel, the endothelial cells were incubated in 37°C for 60 minutes in PBS containing tetramethylrhodamine isothiocyanate conjugated albumin (TRITC-albumin). Thereafter, the cell morphology and the albumin uptake were observed by a confocal laser scanning microscope (CLSM). In a low shear stress area (stagnant and reattachment areas), the cells aligned randomly. In a high shear stress area (reversal and fully developed areas), the cells were elongated and aligned to flow direction. In low-shear-stress and high-shear-stress gradient areas (reattachment areas), the amount of albumin uptake into the cells was the largest in all areas. These data indicate that shear stress and shear stress gradient affect the endothelial cell morphology and the albumin uptake into endothelial cells.

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