AMP kinase activation by Omega-3 polyunsaturated fatty acid protects the retina against ischemic insult: An in vitro and in vivo study.

Autor: Dátilo MN; Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil., Formigari GP; Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil., de Faria JBL; Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil., de Faria JML; Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address: lopesdefariajm@gmail.com.
Jazyk: angličtina
Zdroj: Experimental eye research [Exp Eye Res] 2023 Jan; Vol. 226, pp. 109345. Date of Electronic Publication: 2022 Dec 09.
DOI: 10.1016/j.exer.2022.109345
Abstrakt: Purpose: To investigate the possible beneficial effects of omega-3 polyunsaturated fatty acids (ω3-PUFAs) in ischemic retinal angiogenesis and whether AMP-activated protein kinase (AMPK) is involved.
Methods: Human retinal microvascular endothelial cells (hRMECs) were exposed to dimethyloxalylglycine (DMOG), a hypoxia-inducible factor hydroxylase inhibitor, in the presence or absence of docosahexaenoic acid (DHA) and small interfering RNA (siRNA) for AMPKα for 24 h. Ischemic factors, endothelial mesenchymal transition marker, endothelial barrier integrity, cell migration, and tube formation were evaluated. Neonatal AMPKα 2 -/- and control wild-type (WT) mice were submitted to an oxygen-induced retinopathy (OIR) protocol; their nursing mother mice were either fed ω3-PUFAs or not. In the end, ischemic markers and endothelial cell proliferation were evaluated in neonatal mouse retinal tissue through immunohistochemical or immunofluorescent assays among all studied groups.
Results: Cells exposed to DMOG displayed increased expressions of hypoxic and endothelial mesenchymal transition (vimentin) markers and barrier disarrangement of Zonula Occludens-1 compared to the control, accompanied by increased cellular migration and tube formation (p < 0.05). AMPK activity was significantly decreased. Supplementation with DHA restored the mentioned alterations compared to DMOG (p<0.05). In siRNA AMPKα -treated cells, the beneficial effects observed with DHA were abolished. DHA upregulated G-protein receptor-120 (GPR120), which promptly increased intracellular levels of calcium (p ≤ 0.001), which consequently increased Calcium/calmodulin-dependent protein kinase kinase β expression (CaMKKβ) thus phosphorylating AMPK Thr172 . AMPKα 2 -/- and wild-type (WT) OIR mice exhibited similar retinal ischemic changes, and the oral supplementation with ω3-PUFA efficiently prevented the noticed ischemic alterations only in WT mice, suggesting that AMPKα 2 is pivotal in the protective effects of ω3-PUFA.
Conclusions: ω3-PUFAs protect the retina from the effects of ischemic conditions, and this effect occurs via the GPR120-CaMKKβ-AMPK axis. A better understanding of this mechanism might improve the control of pathological angiogenesis in retinal ischemic diseases.
Competing Interests: Declaration of competing interest The authors declare no competing interests in this study.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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