Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia.

atherosclerosis hyperlipidemia inflammation platelets thrombin

Journal

Research and practice in thrombosis and haemostasis
ISSN: 2475-0379
Titre abrégé: Res Pract Thromb Haemost
Pays: United States
ID NLM: 101703775

Informations de publication

Date de publication:
Jan 2024
Historique:
received: 16 03 2023
revised: 16 09 2023
accepted: 19 09 2023
medline: 16 1 2024
pubmed: 16 1 2024
entrez: 16 1 2024
Statut: epublish

Résumé

Hyperlipidemia is associated with chronic inflammation and thromboinflammation. This is an underlying cause of several cardiovascular diseases, including atherosclerosis. In diseased blood vessels, rampant thrombin generation results in the initiation of the coagulation cascade, activation of platelets, and endothelial cell dysfunction. Coagulation factor (F) XI represents a promising therapeutic target to reduce thromboinflammation, as it is uniquely positioned at an intersection between inflammation and thrombin generation. This study aimed to investigate the role of FXI in promoting platelet and endothelial cell activation in a model of hyperlipidemia. Nonhuman primates (NHPs) were fed a standard chow diet (lean, Obese NHPs demonstrated increased sensitivity for platelet P-selectin expression and phosphatidylserine exposure in response to platelet GPVI or PAR agonists compared with lean NHPs. Obese NHPs exhibited elevated levels of C-reactive protein, cathepsin D, and myeloperoxidase compared with lean NHPs. Following pharmacological inhibition of FIX activation by FXIa, platelet priming for activation by GPVI or PAR agonists, C-reactive protein levels, and endothelial VCAM-1 levels were reduced in obese NHPs. FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction.

Sections du résumé

Background UNASSIGNED
Hyperlipidemia is associated with chronic inflammation and thromboinflammation. This is an underlying cause of several cardiovascular diseases, including atherosclerosis. In diseased blood vessels, rampant thrombin generation results in the initiation of the coagulation cascade, activation of platelets, and endothelial cell dysfunction. Coagulation factor (F) XI represents a promising therapeutic target to reduce thromboinflammation, as it is uniquely positioned at an intersection between inflammation and thrombin generation.
Objectives UNASSIGNED
This study aimed to investigate the role of FXI in promoting platelet and endothelial cell activation in a model of hyperlipidemia.
Methods UNASSIGNED
Nonhuman primates (NHPs) were fed a standard chow diet (lean,
Results UNASSIGNED
Obese NHPs demonstrated increased sensitivity for platelet P-selectin expression and phosphatidylserine exposure in response to platelet GPVI or PAR agonists compared with lean NHPs. Obese NHPs exhibited elevated levels of C-reactive protein, cathepsin D, and myeloperoxidase compared with lean NHPs. Following pharmacological inhibition of FIX activation by FXIa, platelet priming for activation by GPVI or PAR agonists, C-reactive protein levels, and endothelial VCAM-1 levels were reduced in obese NHPs.
Conclusion UNASSIGNED
FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction.

Identifiants

DOI: 10.1016/j.rpth.2023.102276 PMID: 38226339 PMC: PMC10788631
pubmed: 38226339
doi: 10.1016/j.rpth.2023.102276
pii: S2475-0379(23)05704-7
pmc: PMC10788631
doi:

Types de publication

Journal Article

Langues

eng

Pagination

102276

Informations de copyright

© 2023 The Authors.

Auteurs

Tia C L Kohs (TCL)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.

Helen H Vu (HH)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.

Kelley R Jordan (KR)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.

Iván Parra-Izquierdo (I)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.

Monica T Hinds (MT)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.

Joseph J Shatzel (JJ)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Division of Hematology and Oncology, Oregon Health & Science University, Portland, Oregon, USA.

Paul Kievit (P)

Division of Cardiometabolic Health, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.

Terry K Morgan (TK)

Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, Oregon, USA.

Samuel Tassi Yunga (ST)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.

Thuy T M Ngo (TTM)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA.

Joseph E Aslan (JE)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon, USA.

Michael Wallisch (M)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Aronora, Inc, Portland, Oregon, USA.

Christina U Lorentz (CU)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Aronora, Inc, Portland, Oregon, USA.

Erik I Tucker (EI)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Aronora, Inc, Portland, Oregon, USA.

David Gailani (D)

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Jonathan R Lindner (JR)

Division of Cardiovascular Medicine and Robert M. Berne Cardiovascular Research Institute, University of Virginia, Charlottesville, Virginia, USA.

Cristina Puy (C)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.

Owen J T McCarty (OJT)

Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Division of Hematology and Oncology, Oregon Health & Science University, Portland, Oregon, USA.

Classifications MeSH