Cysteine Leukotriene Receptor Antagonist-Montelukast Effects on Diabetic Retinal Microvascular Endothelial Cells Curtail Autophagy.

Autor:	Awad AM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Mansoura, Egypt., Seetharaman ATM; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States., Hossain MS; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States., Elshaer SL; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt., Abdelaziz RR; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Mansoura, Egypt., Nader MA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Mansoura, Egypt., Gangaraju R; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States.; Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States.
Jazyk:	angličtina
Zdroj:	Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2024 Nov 04; Vol. 65 (13), pp. 15.
DOI:	10.1167/iovs.65.13.15
Abstrakt:	Purpose: Diabetic macular edema (DME) is the primary cause of vision impairment in diabetic retinopathy (DR) patients. A previous study has shown the efficacy of montelukast, a cysteinyl leukotriene receptor (CysLTR)1 antagonist, in a diabetic mouse model. This study aims to understand the CysLTR1 signaling in retinal endothelial cells and the impact of montelukast. Methods: Primary human retinal microvascular endothelial cells (HRECs) challenged with 20 ng/mL TNF-α and 30 mM D-glucose (D-glu) for six to 24 hours served as a model of endothelial activation. HRECs were incubated with L-glucose (L-glu) as an osmotic control. CysLTR1 knockdown and montelukast pretreatment assessed CysLTR1 antagonism. Gene expression, protein expression, and cell-permeable dyes were utilized to measure autophagy and inflammation. Transendothelial electrical resistance (TER) and transendothelial migration of mononuclear leukocytes across HRECs monolayer were measured as a functional assessment of vascular permeability. Results: Endothelial activation induced by hyperglycemia and inflammation increased CysLTR1 expression, triggering autophagy within two to six hours, IL-1β production, loss of junction integrity, decreased TER, and increased leukocyte migration within six to 24 hours. Pretreatment with montelukast effectively alleviated these effects, demonstrating its dependence on CysLTR1. Conclusions: Dysfunctional retinal endothelium initiates a self-reinforcing loop of inflammation, autophagy, and compromised integrity associated with heightened CysLTR1 levels. The antagonistic effect of montelukast against CysLTR1 effectively mitigates these detrimental changes. This study reveals CysLTR1 as a potential therapeutic target in treating DME and offers a novel strategy to mitigate detrimental changes in DR.
Databáze:	MEDLINE
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