Exogenous hydrogen sulfide inhibits apoptosis by regulating endoplasmic reticulum stress–autophagy axis and improves myocardial reconstruction after acute myocardial infarction

2020 ◽  
Vol 52 (12) ◽  
pp. 1325-1336
Author(s):  
Yaling Li ◽  
Maojun Liu ◽  
Jiali Yi ◽  
Xiong Song ◽  
Xia Zheng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Hydrogen Sulfide ◽  
Er Stress ◽  
Inhibitory Effect ◽  
Myocardial Apoptosis ◽  
Apoptosis Protein ◽  
Related Proteins

Abstract During acute myocardial infarction, endoplasmic reticulum (ER) stress-induced autophagy and apoptosis have been shown as important pathogeneses of myocardial reconstruction. Importantly, hydrogen sulfide (H2S), as a third endogenous gas signaling molecule, exerts strong cytoprotective effect on anti-ER stress, autophagy regulation and antiapoptosis. Here, we showed that H2S treatment inhibits apoptosis by regulating ER stress–autophagy axis and improves myocardial reconstruction after acute myocardial infarction. We found that H2S intervention improved left ventricle function, reduced glycogen deposition in myocardial tissue mesenchyme, and inhibited apoptosis. Moreover, the expressions of fibrosis indicators (Col3a1 and Col1a2), ER stress-related proteins (CHOP and BIP/ERP78), autophagy-related proteins (Beclin and ATG5), apoptosis protein (Bax), as well as fibrosis protein Col4a3bp were all decreased after treatment with H2S. H2S administration also maintained MMP/TIMP balance. Mechanistically, H2S activated the PI3K/AKT signaling pathway. In addition, H2S treatment also reduced the expressions of ER stress–related proteins, autophagy-related proteins, and apoptins in in vitro experiments. Interestingly, activation of ER stress–autophagy axis could reverse the inhibitory effect of H2S on myocardial apoptosis. Altogether, these results suggested that exogenous H2S suppresses myocardial apoptosis by blocking ER stress–autophagy axis, which in turn reverses cardiac remodeling after myocardial infarction.

Cortistatin Improves Cardiac Function After Acute Myocardial Infarction in Rats by Suppressing Myocardial Apoptosis and Endoplasmic Reticulum Stress

2016 ◽  
Vol 22 (1) ◽  
pp. 83-93 ◽  
Author(s):  
Zhi-Yu Shi ◽  
Yue Liu ◽  
Li Dong ◽  
Bo Zhang ◽  
Meng Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Cardiac Function ◽  
Er Stress ◽  
Rat Model ◽  
Caspase 3 ◽  
Apoptotic Pathway ◽  
Myocardial Apoptosis ◽  
Glucose Regulated Protein

Objectives: The endoplasmic reticulum (ER) stress-induced apoptotic pathway is associated with the development of acute myocardial infarction (AMI). Cortistatin (CST) is a novel bioactive peptide that inhibits apoptosis-related injury. Therefore, we investigated the cardioprotective effects and potential mechanisms of CST in a rat model of AMI. Methods: Male Wistar rats were randomly divided into sham, AMI, and AMI + CST groups. Cardiac function and the degree of infarction were evaluated by echocardiography, cardiac troponin I activity, and 2,3,5-triphenyl-2H-tetrazolium chloride staining after 7 days. The expression of CST, ER stress markers, and apoptotic markers was examined using immunohistochemistry and Western blotting. Results: Compared to the AMI group, the AMI + CST group exhibited markedly better cardiac function and a lower degree of infarction. Electron microscopy and terminal deoxynucleotidyl transferase dUTP nick end labeling confirmed that myocardial apoptosis occurred after AMI. Cortistatin treatment reduced the expression of caspase 3, cleaved caspase 3, and Bax (proapoptotic proteins) and promoted the expression of Bcl-2 (antiapoptotic protein). In addition, the reduced expression of glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding proteins homologous protein, and caspase 12 indicated that ER stress and the apoptotic pathway associated with ER stress were suppressed. Conclusions: Exogenous CST has a notable cardioprotective effect after AMI in a rat model in that it improves cardiac function by suppressing ER stress and myocardial apoptosis.

scholarly journals Network pharmacology-based identification of major component of Angelica sinensis and its action mechanism for the treatment of acute myocardial infarction

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Xiaowei Niu ◽  
Jingjing Zhang ◽  
Jinrong Ni ◽  
Runqing Wang ◽  
Weiqiang Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Er Stress ◽  
Heart Function ◽  
Network Pharmacology ◽  
Angelica Sinensis ◽  
Peroxisome Proliferator ◽  
Multiple Targets

Background: To decipher the mechanisms of Angelica sinensis for the treatment of acute myocardial infarction (AMI) using network pharmacology analysis. Methods: Databases were searched for the information on constituents, targets, and diseases. Cytoscape software was used to construct the constituent–target–disease network and screen the major targets, which were annotated with the DAVID (Database for Annotation, Visualization and Integrated Discovery) tool. The cardioprotective effects of Angelica sinensis polysaccharide (ASP), a major component of A. sinensis, were validated both in H9c2 cells subjected to simulated ischemia by oxygen and glucose deprivation and in rats with AMI by ligation of the left anterior coronary artery. Results: We identified 228 major targets against AMI injury for A. sinensis, which regulated multiple pathways and hit multiple targets involved in several biological processes. ASP significantly decreased endoplasmic reticulum (ER) stress-induced cell death both in vitro and in vivo. In ischemia injury rats, ASP treatment reduced infarct size and preserved heart function. ASP enhanced activating transcription factor 6 (ATF6) activity, which improved ER-protein folding capacity. ASP activated the expression of p-AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Additionally, ASP attenuated levels of proinflammatory cytokines and maintained a balance in the oxidant/antioxidant levels after AMI. Conclusion:In silico analysis revealed the associations between A. sinensis and AMI through multiple targets and several key signaling pathways. Experimental data indicate that ASP protects the heart against ischemic injury by activating ATF6 to ameliorate the detrimental ER stress. ASP’s effects could be mediated via the activation of AMPK-PGC1α pathway.

scholarly journals Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress

2016 ◽  
Vol 310 (9) ◽  
pp. C755-C763 ◽  
Author(s):  
Mingfang Jiang ◽  
Qiang Yun ◽  
Feng Shi ◽  
Guangming Niu ◽  
Yang Gao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Target Genes ◽  
Binding Protein ◽  
Quantitative Polymerase Chain Reaction ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Stress Signaling

Endoplasmic reticulum (ER) stress has been linked to the pathogenesis of Parkinson's disease (PD). However, the role of microRNAs (miRNAs) in this process involved in PD remains poorly understood. Recent studies indicate that miR-384-5p plays an important role for cell survival in response to different insults, but the role of miR-384-5p in PD-associated neurotoxicity remains unknown. In this study, we investigated the role of miR-384-5p in an in vitro model of PD using dopaminergic SH-SY5Y cells treated with rotenone. We found that miR-384-5p was persistently induced by rotenone in neurons. Also, the inhibition of miR-384-5p significantly suppressed rotenone-induced neurotoxicity, while overexpression of miR-384-5p aggravated rotenone-induced neurotoxicity. Through bioinformatics and dual-luciferase reporter assay, miR-384-5p was found to directly target the 3′-untranslated region of glucose-regulated protein 78 (GRP78), the master regulator of ER stress sensors. Quantitative polymerase chain reaction and Western blotting analysis showed that miR-384-5p negatively regulated the expression of GRP78. Inhibition of miR-384-5p remarkably suppressed rotenone-evoked ER stress, which was evident by a reduction in the phosphorylation of activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1α). The downstream target genes of ER stress including CCAAT/enhancer-binding protein-homologous protein (CHOP) and X box-binding protein-1 (XBP-1) were also decreased by the miR-384-5p inhibitor. In contrast, overexpression of miR-384-5p enhanced ER stress signaling. In addition, knockdown of GRP78 significantly abrogated the inhibitory effect of miR-384-5p inhibitors on cell apoptosis and ER stress signaling. Moreover, we observed a significant increase of miR-384-5p expression in primary neurons induced by rotenone. Taken together, our results suggest that miR-384-5p mediated ER stress by negatively regulating GRP78 and that miR-384-5p inhibition might be a novel and promising approach for the treatment of PD.

scholarly journals Interactions between Endoplasmic Reticulum Stress and Autophagy: Implications for Apoptosis and Neuroplasticity-Related Proteins in Palmitic Acid-Treated Prefrontal Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Xiangli Xue ◽  
Feng Li ◽  
Ming Cai ◽  
Jingyun Hu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Sprague Dawley ◽  
Related Proteins ◽  
Phenylbutyric Acid

Lipotoxicity of palmitic acid (PA) or high-fat diets has been reported to increase endoplasmic reticulum (ER) stress and autophagy in peripheral tissue as well as apoptotic cell death. It also can lead to an AD-like pathological pattern. However, it has been unknown that PA-induced ER stress and autophagy are involved in the regulation of neuroplastic abnormalities. Here, we investigated the roles of ER stress and autophagy in apoptosis and neuroplasticity-related protein expression in PA-treated prefrontal cells. Prefrontal cells dissected from newborn Sprague-Dawley rats were treated with PA compound with ER stress inhibitor 4-phenylbutyric acid (4-PBA) and autophagy inhibitor 3-methyladenine (3-MA) or PA alone. PA promoted ER stress and autophagy and also cause apoptosis as well as a decline in the expression of neuroplasticity-related proteins. Inhibition of ER stress decreased the expressions of neuroplasticity-related proteins and reduced autophagy activation and apoptosis in PA-treated prefrontal cells. Inhibition of autophagy exacerbated apoptosis and enhanced ER stress in PA-treated prefrontal cells. The present study illustrated that both ER stress and autophagy could be involved in apoptosis and decreased neuroplasticity-related proteins, and the interaction between ER stress and autophagy may play a critical role in apoptosis in PA-treated prefrontal cells. Our results provide new insights into the molecular mechanisms in vitro of lipotoxicity in obesity-related cognitive dysfunction.

scholarly journals Selenoprotein V Protects Against Oxidative Stress, Endoplasmic Reticulum Stress, and Apoptosis

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1858-1858
Author(s):  
Xu Zhang ◽  
Wei Xiong ◽  
Jiaqiang Huang ◽  
Xin Gen Lei
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Caspase 9 ◽  
Funding Sources ◽  
Control Plasmid ◽  
Selenoprotein V ◽  
Related Proteins

Abstract Objectives Selenoprotein V (SELENOV) contains a thioredoxin-like fold and a conserved CxxU motif with a potential redox function. Three experiments were performed to assess its in vivo and in vitro roles and mechanisms in coping with different oxidant insults. Methods In Expt.1, SELENOV knockout (KO) and wildtype (WT) mice (male, 8-wk old) were given an IP injection of saline, diquat (DQ, 12.5 mg/kg), or acetaminophen (APAP, 300 mg/kg) (n = 10), and killed 5 h after the injection to collect liver and blood. In Expt. 2, primary hepatocytes were isolated from the 2 genotypes, cultured in complete Williams's medium E, and treated with DQ (0, 0.25 and 0.75 mM) and APAP (0, 1, 3, and 6 mM) for 12 h. In Expt. 3, 293 T cells were transfected with a control plasmid (GFP) or the plasmid containing Selenov gene (full length, OE) and treated with APAP (0, 1, 2, and 4 mM) for 24 h or H2O2 (0.1, 0.2, and 0.4 mM) for 12 h. Results In Expt. 1, the DQ and APAP injections caused greater (P < 0.05) rises in serum alanine aminotransferase activities, hepatic malondialdehyde (MDA) and carbonyl contents, endoplasmic reticulum (ER) stress-related proteins (BIP and CHOP), apoptosis-related proteins (FAK and caspase 9), and 3-nitrotyrosine, along with lower total anti-oxidizing-capability (T-AOC) and severer hepatocyte necrosis in the central lobular areas, in the KO than in the WT. In Expt. 2, the DQ and APAP treatments induced elevated (P < 0.05) cell death (20–40%), MDA contents (25–35%), and decreased (P < 0.05) T-AOC (50–65%) in the KO hepatocytes than in the WT cells. The KO hepatocytes treated with APAP displayed a sharp decline (P < 0.05) in cellular total respiration ability than the WT cells. In Expt. 3, the OE cells had greater viability and T-AOC and lower reactive oxygen species, MDA, and carbonyl contents after the APAP and H2O2 exposures (all at P < 0.05) than the controls. Moreover, the OE cells had greater (P < 0.05) redox enzyme activities (GPX, TrxR, and SOD), and lower (P < 0.05) expressions of ER stress-related genes (Atf4, Atf6, Bip, Xpp1t, Xbp1s, and Chop) and proteins (BIP, CHOP, FAK, caspase 9) than the controls after the treatment of H2O2 (0.4 mM). Conclusions Our data revealed the in vivo and in vitro roles and mechanisms of SELENOV in protecting against oxidative stress, ER stress, and apoptosis induced by pro-oxidants. Funding Sources This research is supported in part by an NSFC grant #31,320,103,920.

Exposure to triptolide affects follicle development in NIH mice

2016 ◽  
Vol 36 (1) ◽  
pp. 82-92 ◽  
Author(s):  
Y Zeng ◽  
H Sun ◽  
Y Li ◽  
M Shao ◽  
P Han ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Estrous Cycle ◽  
Initiation Factor ◽  
Immunohistochemical Method ◽  
Terminal Deoxynucleotidyl Transferase ◽  
High Dose ◽  
Apoptosis Protein ◽  
Therapeutic Doses ◽  
Related Proteins

Triptolide (TPL) is a main active compound isolated from Tripterygium wilfordii Hook f. Despite its positive therapeutic effect, the female reproductive toxicity of TPL is still the bottleneck of clinical application. The study was designed to investigate the adverse effects on mice ovary and underlying mechanism of TPL. Adult female NIH mice were treated with two therapeutic doses of TPL (25 and 50 μg/kg/d) for 50 days, respectively. Mice estrous cycle was detected by vaginal cytology method. Half mice from each group were selected randomly to perform superovulation. Quality and quantity of ovulated eggs were evaluated. Other mice from each group were executed for morphological study. Ovarian histological sections were stained by H&E staining for ovarian pathologic detection and follicular counts. Apoptotic granulosa cell (GC) was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Endoplasmic reticulum (ER) stress-related proteins and antiapoptotic X-linked inhibitor of apoptosis protein (XIAP) were detected by immunohistochemical method. Two doses of TPL resulted in estrous cycle disorder and follicles in development reservoir impairment. Quality and quantity of mice ovulated eggs significantly decreased after TPL treatment. Ovarian pathologic examination revealed TPL-induced TUNEL-positive GCs increase and ER stress–related proteins (78-kDa glucose-regulated protein, p-protein kinase-like endoplasmic reticulum kinase, p-eukaryotic initiation factor 2α, and CCAAT/enhancer binding protein homologous protein) expression upregulation. Meanwhile, the expression of antiapoptosis protein XIAP in mice ovary was obviously inhibited by TPL. Our results may demonstrate that therapeutic doses of TPL can injure ovary function, but there is no difference between high-dose and low-dose groups. GCs apoptosis by ER stress pathway and antiapoptotic function impairment may partly mediate TPL-induced ovary toxicity.

scholarly journals ZYZ-803 Mitigates Endoplasmic Reticulum Stress-Related Necroptosis after Acute Myocardial Infarction through Downregulating the RIP3-CaMKII Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Lingling Chang ◽  
Zhijun Wang ◽  
Fenfen Ma ◽  
Bahieu Tran ◽  
Rui Zhong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Signaling Pathway ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Interacting Protein

Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide, and both cardiac necroptosis and endoplasmic reticulum stress (ERS) have been involved in the pathophysiology of AMI. ZYZ-803 is a hybrid molecule of a dual donor for gasotransmitters H2S and NO. The aim of the present study is to investigate the antinecroptosis role and potential mechanisms of ZYZ-803 in the setting of ERS during AMI injury. In vivo, ZYZ-803 preserves cardiac function and reduces infarct size significantly after 24-hour left coronary artery ligation through revising H2S and NO imbalance. In addition, ZYZ-803 relieves ERS and necroptosis in an AMI heart. In vitro, ZYZ-803 ameliorates ERS-related necroptosis induced by tunicamycin, and such effect has been depending on the receptor-interacting protein 3- (RIP3-) Ca2+-calmodulin-dependent protein kinase (CaMKII) signaling pathway. These findings have identified a novel antinecroptosis potential of ZYZ-803, providing a valuable candidate for cardioprotection in acute myocardial ischemia.

Pharmacokinetics and Haemostatic Status During Consecutive Infusions of Recom binant Tissue-Type Plasminogen Activator in Patients with Acute Myocardial Infarction

1989 ◽  
Vol 61 (03) ◽  
pp. 497-501 ◽  
Author(s):  
E Seifried ◽  
P Tanswell ◽  
D Ellbrück ◽  
W Haerer ◽  
A Schmidt
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Plasminogen Activator ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Precise Control ◽  
Type Plasminogen Activator

SummaryPharmacokinetics and systemic effects of recombinant tissue type plasminogen activator (rt-PA) were determined during coronary thrombolysis in 12 acute myocardial infarction patients using a consecutive intravenous infusion regimen. Ten mg rt-PA were infused in 2 minutes resulting in a peak plasma concentration (mean ±SD) of 3310±950 ng/ml, followed by 50 mg in 1 h and 30 mg in 1.5 h yielding steady state plasma levels of. 2210±470 nglml and 930±200 ng/ml, respectively. All patients received intravenous heparin. Total clearance of rt-PA was 380±74 ml/min, t,½α was 3.6±0.9 min and t,½β was 16±5.4 min.After 90 min, in plasma samples containing anti-rt-PA-IgG to inhibit in vitro effects, fibrinogen was decreased to 54%, plasminogen to 52%, α2-antiplasmin to 25%, α2-macroglobulin to 90% and antithrombin III to 85% of initial values. Coagulation times were prolonged and fibrin D-dimer concentrations increased from 0.40 to 2.7 μg/ml. It is concluded that pharmacokinetics of rt-PA show low interpatient variability and that its short mean residence time in plasma allows precise control of therapy. Apart from its moderate effect on the haemostatic system, rt-PA appears to lyse a fibrin pool in addition to the coronary thrombus.

Testicular Injury Attenuated by Rapamycin Through Induction of Autophagy and Inhibition of Endoplasmic Reticulum Stress in Streptozotocin- Induced Diabetic Rats

2019 ◽  
Vol 19 (5) ◽  
pp. 665-675 ◽  
Author(s):  
Wenjiao Shi ◽  
Zhixin Guo ◽  
Ruixia Yuan
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protective Effect ◽  
Er Stress ◽  
B Cell Lymphoma ◽  
Diabetic Rats ◽  
Pathological Changes ◽  
Rapamycin Treatment ◽  
Related Proteins

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

scholarly journals Neutrophil extracellular traps induce MCP-1 release from endothelial cells at the plaque rupture site in acute myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Ondracek ◽  
T.M Hofbauer ◽  
A Mangold ◽  
T Scherz ◽  
V Seidl ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endothelial Cells ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Coronary Intervention ◽  
Neutrophil Extracellular Traps ◽  
Funding Source ◽  
Extracellular Traps

Abstract Introduction Leukocyte-mediated inflammation is crucial in acute myocardial infarction (AMI). We recently observed that neutrophil extracellular traps (NETs) are increased at the culprit site, promoting activation and differentiation of fibrocytes, cells with mesenchymal and leukocytic properties. Fibrocyte migration is mediated by monocyte chemoattractant protein (MCP)-1 and C-C chemokine receptor type 2 (CCR2). We investigated the interplay between NETs, fibrocyte function, and MCP-1 in AMI. Methods Culprit site and femoral blood of AMI patients was drawn during percutaneous coronary intervention. We characterized CCR2 expression of fibrocytes by flow cytometry. MCP-1 and the NET marker citrullinated histone H3 (citH3) were measured by ELISA. Fibrocytes were treated in vitro with MCP-1. Human coronary arterial endothelial cells (hCAECs) were stimulated with isolated NETs, and MCP-1 was measured by ELISA and qPCR. The influence of MCP-1 on NET formation in vitro was assessed using isolated neutrophils. Results We have included 50 consecutive AMI patients into the study. NETs and concentrations of MCP-1 were increased at the CLS. NET stimulation of hCAECs induced MCP-1 on mRNA and protein level. Increasing MCP-1 gradient was associated with fibrocyte accumulation at the site of occlusion. In the presence of higher MCP-1 these fibrocytes expressed proportionally less CCR2 than peripheral fibrocytes. In vitro, MCP-1 dose-dependently decreased fibrocyte CCR2 and reduced ex vivo NET release of healthy donor neutrophils. Conclusions NETs induce endothelial MCP-1 release, presumably promoting a chemotactic gradient for leukocyte and fibrocyte migration. MCP-1 mediated inhibition of NET formation could point to a negative feedback loop. These data will shed light on vascular healing. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund

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