Biomarkers of Endothelial Cell Activation Serve as Potential Surrogate Markers for Drug-induced Vascular Injury

Drug-induced vascular injury (DIVI) is a nonclinical finding that often confounds the toxicological evaluation of investigational drugs, but there is an absence of qualified biomarkers that can be used to detect and monitor its appearance in animals and patients during drug development and clinical use. It is well known that endothelial cell (EC) activation plays a key role in the expression and evolution of DIVI, and the various immunological and inflammatory factors involved in its expression may serve as potential biomarker candidates. Activated ECs change their morphology and gene expression, generating endothelial adhesion molecules, pro-coagulant molecules, cytokines, chemokines, vasodilators, nitric oxide, and acute-phase reactants. This review provides a brief historical background of EC activation and the search for biomarkers of early EC activation for monitoring DIVI. At present, no biomarkers of EC activation have been qualified to predict DIVI in the nonclinical or clinical context, and a robust pathologic foundation for their use is still lacking. We propose three categories of EC activation biomarkers: recommended surrogate markers, potentially useful markers, and emerging candidate markers. This review alerts pharmaceutical companies, research institutions, and regulatory agencies to the continuing need for reliable biomarkers of EC activation in drug development.

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Biomarkers of endothelial cell activation: Candidate markers for drug-induced vasculitis in patients or drug-induced vascular injury in animals

Vascular Pharmacology ◽

10.1016/j.vph.2011.09.002 ◽

2012 ◽

Vol 56 (1-2) ◽

pp. 14-25 ◽

Cited By ~ 14

Author(s):

Jun Zhang ◽

Joseph P. Hanig ◽

Albert F. De Felice

Keyword(s):

Endothelial Cell ◽

Vascular Injury ◽

Cell Activation ◽

Endothelial Cell Activation ◽

Drug Induced

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Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.773473 ◽

2021 ◽

Vol 8 ◽

Author(s):

Keman Xu ◽

Ying Shao ◽

Fatma Saaoud ◽

Aria Gillespie ◽

Charles Drummer ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Activation ◽

Nuclear Dna ◽

Inflammatory Responses ◽

Inflammatory Factors ◽

Secretory Proteins ◽

Human Aortic Endothelial Cell ◽

Endothelial Cell Activation ◽

Knowledge Based ◽

Inflammatory Conditions

To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.

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Adhesion molecule expression and endothelial cell activation in cutaneous leukocytoclastic vasculitis. An immunohistologic and clinical study in 42 patients

Archives of Dermatology ◽

10.1001/archderm.133.4.443 ◽

1997 ◽

Vol 133 (4) ◽

pp. 443-450 ◽

Cited By ~ 10

Author(s):

G. Sais

Keyword(s):

Endothelial Cell ◽

Clinical Study ◽

Adhesion Molecule ◽

Cell Activation ◽

Leukocytoclastic Vasculitis ◽

Adhesion Molecule Expression ◽

Endothelial Cell Activation

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Faculty Opinions recommendation of Loss of DGKε induces endothelial cell activation and death independently of complement activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725276451.793502628 ◽

2014 ◽

Author(s):

Toshiyuki Miyata

Keyword(s):

Endothelial Cell ◽

Complement Activation ◽

Cell Activation ◽

Endothelial Cell Activation

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Platelet disturbances correlate with endothelial cell activation in uncomplicated Plasmodium vivax malaria

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0007656 ◽

2020 ◽

Vol 14 (7) ◽

pp. e0007656

Author(s):

João Conrado Khouri Dos-Santos ◽

João Luiz Silva-Filho ◽

Carla C. Judice ◽

Ana Carolina Andrade Vitor Kayano ◽

Júlio Aliberti ◽

...

Keyword(s):

Endothelial Cell ◽

Plasmodium Vivax ◽

Vivax Malaria ◽

Cell Activation ◽

Endothelial Cell Activation ◽

Plasmodium Vivax Malaria

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Signs of sympathetic and endothelial cell activation in the skin of patients with restless legs syndrome

Sleep Medicine ◽

10.1016/j.sleep.2021.05.044 ◽

2021 ◽

Author(s):

Melanie Bergmann ◽

Anna Heidbreder ◽

Ambra Stefani ◽

Cecilia Raccagni ◽

Elisabeth Brandauer ◽

...

Keyword(s):

Endothelial Cell ◽

Restless Legs Syndrome ◽

Cell Activation ◽

Endothelial Cell Activation ◽

Restless Legs

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OR17 Heme oxygenase-1 modulates HLA class I antibody-dependent endothelial cell activation

Human Immunology ◽

10.1016/j.humimm.2015.07.023 ◽

2015 ◽

Vol 76 ◽

pp. 15

Author(s):

Eva Zilian ◽

Hendry Saragih ◽

Oliver Hiller ◽

Abid Aljabri ◽

Constanca Figueiredo ◽

...

Keyword(s):

Endothelial Cell ◽

Heme Oxygenase ◽

Cell Activation ◽

Hla Class I ◽

Class I ◽

Heme Oxygenase 1 ◽

Endothelial Cell Activation

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Dengue Virus Induces the Expression and Release of Endocan from Endothelial Cells by an NS1–TLR4-Dependent Mechanism

Microorganisms ◽

10.3390/microorganisms9061305 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1305

Author(s):

Carlos Alonso Domínguez-Alemán ◽

Luis Alberto Sánchez-Vargas ◽

Karina Guadalupe Hernández-Flores ◽

Andrea Isabel Torres-Zugaide ◽

Arturo Reyes-Sandoval ◽

...

Keyword(s):

Endothelial Cell ◽

Mrna Expression ◽

Cell Lines ◽

Cell Activation ◽

Dengue Infection ◽

Elevated Serum ◽

Fold Increase ◽

Endothelial Cell Activation ◽

Stimulation Of

A common hallmark of dengue infections is the dysfunction of the vascular endothelium induced by different biological mechanisms. In this paper, we studied the role of recombinant NS1 proteins representing the four dengue serotypes, and their role in promoting the expression and release of endocan, which is a highly specific biomarker of endothelial cell activation. We evaluated mRNA expression and the levels of endocan protein in vitro following the stimulation of HUVEC and HMEC-1 cell lines with recombinant NS1 proteins. NS1 proteins increase endocan mRNA expression 48 h post-activation in both endothelial cell lines. Endocan mRNA expression levels were higher in HUVEC and HMEC-1 cells stimulated with NS1 proteins than in non-stimulated cells (p < 0.05). A two-fold to three-fold increase in endocan protein release was observed after the stimulation of HUVECs or HMEC-1 cells with NS1 proteins compared with that in non-stimulated cells (p < 0.05). The blockade of Toll-like receptor 4 (TLR-4) signaling on HMEC-1 cells with an antagonistic antibody prevented NS1-dependent endocan production. Dengue-infected patients showed elevated serum endocan levels (≥30 ng/mL) during early dengue infection. High endocan serum levels were associated with laboratory abnormalities, such as lymphopenia and thrombocytopenia, and are associated with the presence of NS1 in the serum.

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Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways

Blood ◽

10.1182/blood.v76.12.2520.2520 ◽

1990 ◽

Vol 76 (12) ◽

pp. 2520-2526 ◽

Cited By ~ 543

Author(s):

SJ van Deventer ◽

HR Buller ◽

JW ten Cate ◽

LA Aarden ◽

CE Hack ◽

...

Keyword(s):

Endothelial Cell ◽

Plasminogen Activator ◽

Cell Activation ◽

Plasminogen Activator Inhibitor ◽

Contact System ◽

Initial Increase ◽

Cytokine Release ◽

Endothelial Cell Activation ◽

System A ◽

Von Willebrand

Abstract Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.

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