Leukotriene B4
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Leukotriene B4 : A potential mediator and biomarker for cardiac allograft vasculopathy. / Wang, Dong; Tediashvili, Grigol; Kim, Daniel; Hu, Xiaomeng; Luikart, Helen; Renne, Thomas; Tian, Amy; Nadeau, Kari C; Velden, Joachim; Schrepfer, Sonja; Khush, Kiran K.
In: J HEART LUNG TRANSPL, Vol. 43, No. 8, 08.2024, p. 1336-1347.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Leukotriene B4
T2 - A potential mediator and biomarker for cardiac allograft vasculopathy
AU - Wang, Dong
AU - Tediashvili, Grigol
AU - Kim, Daniel
AU - Hu, Xiaomeng
AU - Luikart, Helen
AU - Renne, Thomas
AU - Tian, Amy
AU - Nadeau, Kari C
AU - Velden, Joachim
AU - Schrepfer, Sonja
AU - Khush, Kiran K
N1 - Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
PY - 2024/8
Y1 - 2024/8
N2 - BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the leading cause of long-term graft failure and mortality after heart transplantation. Effective preventive and treatment options are not available to date, largely because underlying mechanisms remain poorly understood. We studied the potential role of leukotriene B4 (LTB4), an inflammatory lipid mediator, in the development of CAV.METHODS: We used an established preclinical rat CAV model to study the role of LTB4 in CAV. We performed syngeneic and allogeneic orthotopic aortic transplantation, after which neointimal proliferation was quantified. Animals were then treated with Bestatin, an inhibitor of LTB4 synthesis, or vehicle control for 30 days post-transplant, and evidence of graft CAV was determined by histology. We also measured serial LTB4 levels in a cohort of 28 human heart transplant recipients with CAV, 17 matched transplant controls without CAV, and 20 healthy nontransplant controls.RESULTS: We showed that infiltration of the arterial wall with macrophages leads to neointimal thickening and a rise in serum LTB4 levels in our rat model of CAV. Inhibition of LTB4 production with the drug Bestatin prevents development of neointimal hyperplasia, suggesting that Bestatin may be effective therapy for CAV prevention. In a parallel study of heart transplant recipients, we found nonsignificantly elevated plasma LTB4 levels in patients with CAV, compared to patients without CAV and healthy, nontransplant controls.CONCLUSIONS: This study provides key evidence supporting the role of the inflammatory cytokine LTB4 as an important mediator of CAV development and provides preliminary data suggesting the clinical benefit of Bestatin for CAV prevention.
AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the leading cause of long-term graft failure and mortality after heart transplantation. Effective preventive and treatment options are not available to date, largely because underlying mechanisms remain poorly understood. We studied the potential role of leukotriene B4 (LTB4), an inflammatory lipid mediator, in the development of CAV.METHODS: We used an established preclinical rat CAV model to study the role of LTB4 in CAV. We performed syngeneic and allogeneic orthotopic aortic transplantation, after which neointimal proliferation was quantified. Animals were then treated with Bestatin, an inhibitor of LTB4 synthesis, or vehicle control for 30 days post-transplant, and evidence of graft CAV was determined by histology. We also measured serial LTB4 levels in a cohort of 28 human heart transplant recipients with CAV, 17 matched transplant controls without CAV, and 20 healthy nontransplant controls.RESULTS: We showed that infiltration of the arterial wall with macrophages leads to neointimal thickening and a rise in serum LTB4 levels in our rat model of CAV. Inhibition of LTB4 production with the drug Bestatin prevents development of neointimal hyperplasia, suggesting that Bestatin may be effective therapy for CAV prevention. In a parallel study of heart transplant recipients, we found nonsignificantly elevated plasma LTB4 levels in patients with CAV, compared to patients without CAV and healthy, nontransplant controls.CONCLUSIONS: This study provides key evidence supporting the role of the inflammatory cytokine LTB4 as an important mediator of CAV development and provides preliminary data suggesting the clinical benefit of Bestatin for CAV prevention.
U2 - 10.1016/j.healun.2024.04.004
DO - 10.1016/j.healun.2024.04.004
M3 - SCORING: Journal article
C2 - 38670297
VL - 43
SP - 1336
EP - 1347
JO - J HEART LUNG TRANSPL
JF - J HEART LUNG TRANSPL
SN - 1053-2498
IS - 8
ER -