Simvastatin and Benznidazole-Mediated Prevention of Trypanosoma cruzi-Induced Endothelial Activation: Role of 15-epi-lipoxin A4 in the Action of Simvastatin

AbstractChagas disease is a life-threatening disorder caused by the protozoan parasite Trypanosoma cruzi. Parasite-specific antibodies, CD8+ T cells, as well as IFN-γ and nitric oxide (NO) are key elements of the adaptive and innate immunity against the extracellular and intracellular forms of the parasite. Bim is a potent pro-apoptotic member of the Bcl-2 family implicated in different aspects of the immune regulation, such as negative selection of self-reactive thymocytes and elimination of antigen-specific T cells at the end of an immune response. Interestingly, the role of Bim during infections remains largely unidentified. To explore the role of Bim in Chagas disease, we infected WT, Bim+/−, Bim−/− mice with trypomastigotes forms of the Y strain of T. cruzi. Strikingly, our data revealed that Bim−/− mice exhibit a delay in the development of parasitemia followed by a deficiency in the control of parasite load in the bloodstream and a decreased survival compared to WT and Bim+/− mice. At the peak of parasitemia, peritoneal macrophages of Bim−/− mice exhibit decreased NO production, which correlated with a decrease in the pro-inflammatory Small Peritoneal Macrophage (SPM) subset. A similar reduction in NO secretion, as well as in the pro-inflammatory cytokines IFN-γ and IL-6, was also observed in Bim−/− splenocytes. Moreover, an impaired anti-T. cruzi CD8+ T-cell response was found in Bim−/− mice at this time point. Taken together, our results suggest that these alterations may contribute to the establishment of a delayed yet enlarged parasitic load observed at day 9 after infection of Bim−/− mice and place Bim as an important protein in the control of T. cruzi infections.

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The Role of P-Selectin in COVID-19 Coagulopathy: An Updated Review

International Journal of Molecular Sciences ◽

10.3390/ijms22157942 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7942

Author(s):

Chiara Agrati ◽

Alessandra Sacchi ◽

Eleonora Tartaglia ◽

Alessandra Vergori ◽

Roberta Gagliardini ◽

...

Keyword(s):

Endothelial Activation ◽

Cardiovascular Complications ◽

Current State ◽

Activated Platelets ◽

Blood Clots ◽

Severe Infections ◽

Platelet Aggregates ◽

Definition Of ◽

Leucocyte Recruitment

In severe COVID-19, which is characterized by blood clots and neutrophil-platelet aggregates in the circulating blood and different tissues, an increased incidence of cardiovascular complications and venous thrombotic events has been reported. The inflammatory storm that characterizes severe infections may act as a driver capable of profoundly disrupting the complex interplay between platelets, endothelium, and leukocytes, thus contributing to the definition of COVID-19-associated coagulopathy. In this frame, P-selectin represents a key molecule expressed on endothelial cells and on activated platelets, and contributes to endothelial activation, leucocyte recruitment, rolling, and tissue migration. Briefly, we describe the current state of knowledge about P-selectin involvement in COVID-19 pathogenesis, its possible use as a severity marker and as a target for host-directed therapeutic intervention.

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Role of Lipoxygenases and the Lipoxin A4/Annexin 1 Receptor in Ischemia-Reperfusion-Induced Gastric Mucosal Damage in Rats

Pharmacology ◽

10.1159/000244017 ◽

2009 ◽

Vol 84 (5) ◽

pp. 294-299 ◽

Cited By ~ 15

Author(s):

Brigitta M. Peskar ◽

Karlheinz Ehrlich ◽

Rufina Schuligoi ◽

Bernhard A. Peskar

Keyword(s):

Ischemia Reperfusion ◽

Mucosal Damage ◽

Gastric Mucosal Damage ◽

Lipoxin A4 ◽

Annexin 1

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Advances in the understanding of trauma-induced coagulopathy

Blood ◽

10.1182/blood-2016-01-636423 ◽

2016 ◽

Vol 128 (8) ◽

pp. 1043-1049 ◽

Cited By ~ 120

Author(s):

Ronald Chang ◽

Jessica C. Cardenas ◽

Charles E. Wade ◽

John B. Holcomb

Keyword(s):

Animal Studies ◽

Causes Of Death ◽

Endothelial Activation ◽

The United States ◽

Trauma Patients ◽

Platelet Dysfunction ◽

Intracranial Injury ◽

Trauma Induced Coagulopathy ◽

Common Causes

Abstract Ten percent of deaths worldwide are due to trauma, and it is the third most common cause of death in the United States. Despite a profound upregulation in procoagulant mechanisms, one-quarter of trauma patients present with laboratory-based evidence of trauma-induced coagulopathy (TIC), which is associated with poorer outcomes including increased mortality. The most common causes of death after trauma are hemorrhage and traumatic brain injury (TBI). The management of TIC has significant implications in both because many hemorrhagic deaths could be preventable, and TIC is associated with progression of intracranial injury after TBI. This review covers the most recent evidence and advances in our understanding of TIC, including the role of platelet dysfunction, endothelial activation, and fibrinolysis. Trauma induces a plethora of biochemical and physiologic changes, and despite numerous studies reporting differences in coagulation parameters between trauma patients and uninjured controls, it is unclear whether some of these differences may be “normal” after trauma. Comparisons between trauma patients with differing outcomes and use of animal studies have shed some light on this issue, but much of the data continue to be correlative with causative links lacking. In particular, there are little data linking the laboratory-based abnormalities with true clinically evident coagulopathic bleeding. For these reasons, TIC continues to be a significant diagnostic and therapeutic challenge.

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Carboxiterminal pro-endothelin-1 as an endothelial cell biomarker in thrombotic thrombocytopenic purpura

Thrombosis and Haemostasis ◽

10.1160/th15-07-0564 ◽

2016 ◽

Vol 115 (05) ◽

pp. 1034-1043 ◽

Cited By ~ 2

Author(s):

György Sinkovits ◽

Péter Farkas ◽

Dorottya Csuka ◽

Katalin Rázsó ◽

Marienn Réti ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Acute Phase ◽

Complement Activation ◽

Endothelial Activation ◽

Factor H ◽

Healthy Controls ◽

Activation Markers ◽

Thrombocytopenic Purpura ◽

Endothelin 1

SummaryThrombotic thrombocytopenic purpura (TTP) is characterised by the deficiency of the von Willebrand factor (VWF) cleaving protease (ADAMTS-13). Although several observations indicate an important role of endothelial activation in the pathogenesis of TTP, no reliable endothelial activation markers are available in the clinical management of TTP. Our aim was to investigate the presence of endothelial activation in TTP and to determine its connections with disease activity, therapy and complement activation. We enrolled 54 patients (median age 40.5; 44 females) and 57 healthy controls (median age 34; 30 females),VWF antigen, carboxiterminal-pro-endothelin-1 (CT-proET-1), complement Factor H and complement activation products (C3bBbP and SC5b-9) were measured. In both the acute and remission phase of TTP we found increased CT-proET-1 and VWF levels, while Factor H levels decreased compared with healthy controls. In remission, however, the elevated CT-proET-1 levels showed 22 % decrease when compared with the acute phase in paired samples (p=0.0031), whereas no changes for VWF and Factor H levels were observed. We also found positive correlations between CT-proET-1 levels and alternative pathway activation markers (C3bBbP; p=0.0360; r=0.4299). The data we present here demonstrate a role of endothelium activation in patients with acute TTP. The finding that CT-proET-1 levels decreased in remission compared with the acute phase further supports endothelial involvement. In addition, we show that endothelial activation also correlated with the activation of the alternative complement pathway. The data suggest that complement and endothelium activation jointly contribute to the development of TTP episodes in patients with predisposition to TTP.Supplementary Material to this article is available online at www.thrombosis-online.com.

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The Role of the Trypanosoma cruzi TcNRBD1 Protein in Translation

PLoS ONE ◽

10.1371/journal.pone.0164650 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0164650 ◽

Cited By ~ 5

Author(s):

Camila Oliveira ◽

Paulo Costa Carvalho ◽

Lysangela Ronalte Alves ◽

Samuel Goldenberg

Keyword(s):

Trypanosoma Cruzi

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Posttreatment with Aspirin-Triggered Lipoxin A4 Analog Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice: The Role of Heme Oxygenase-1

Anesthesia & Analgesia ◽

10.1213/01.ane.0000252414.00363.c4 ◽

2007 ◽

Vol 104 (2) ◽

pp. 369-377 ◽

Cited By ~ 80

Author(s):

Sheng-Wei Jin ◽

Li Zhang ◽

Qin-Quan Lian ◽

Dong Liu ◽

Ping Wu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Lipoxin A4

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The role of Lipoxin A4 in endometrial biology and endometriosis

Mucosal Immunology ◽

10.1038/mi.2013.9 ◽

2013 ◽

Vol 6 (3) ◽

pp. 439-450 ◽

Cited By ~ 19

Author(s):

G O Canny ◽

B A Lessey

Keyword(s):

Lipoxin A4

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METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2025070118 ◽

2021 ◽

Vol 118 (7) ◽

pp. e2025070118

Author(s):

Chian-Shiu Chien ◽

Julie Yi-Shuan Li ◽

Yueh Chien ◽

Mong-Lien Wang ◽

Aliaksandr A. Yarmishyn ◽

...

Keyword(s):

Blood Flow ◽

Endothelial Activation ◽

Plaque Formation ◽

Rna Modification ◽

Branch Points ◽

Monocyte Adhesion ◽

Down Regulation ◽

Hemodynamic Forces

Atherosclerosis is characterized by the plaque formation that restricts intraarterial blood flow. The disturbed blood flow with the associated oscillatory stress (OS) at the arterial curvatures and branch points can trigger endothelial activation and is one of the risk factors of atherosclerosis. Many studies reported the mechanotransduction related to OS and atherogenesis; however, the transcriptional and posttranscriptional regulatory mechanisms of atherosclerosis remain unclear. Herein, we investigated the role of N6-methyladenosine (m6A) RNA methylation in mechanotransduction in endothelial cells (ECs) because of its important role in epitranscriptome regulation. We have identified m6A methyltransferase METTL3 as a responsive hub to hemodynamic forces and atherogenic stimuli in ECs. OS led to an up-regulation of METTL3 expression, accompanied by m6A RNA hypermethylation, increased NF-κB p65 Ser536 phosphorylation, and enhanced monocyte adhesion. Knockdown of METTL3 abrogated this OS-induced m6A RNA hypermethylation and other manifestations, while METTL3 overexpression led to changes resembling the OS effects. RNA-sequencing and m6A-enhanced cross-linking and immunoprecipitation (eCLIP) experiments revealed NLRP1 and KLF4 as two hemodynamics-related downstream targets of METTL3-mediated hypermethylation. The METTL3-mediated RNA hypermethylation up-regulated NLRP1 transcript and down-regulated KLF4 transcript through YTHDF1 and YTHDF2 m6A reader proteins, respectively. In the in vivo atherosclerosis model, partial ligation of the carotid artery led to plaque formation and up-regulation of METTL3 and NLRP1, with down-regulation of KLF4; knockdown of METTL3 via repetitive shRNA administration prevented the atherogenic process, NLRP3 up-regulation, and KLF4 down-regulation. Collectively, we have demonstrated that METTL3 serves a central role in the atherogenesis induced by OS and disturbed blood flow.

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