ABCA1 Regulates IOP by Modulating Cav1/eNOS/NO Signaling Pathway.
Hu Chunchun, Niu Liangliang, Li Liping, Song Maomao, Zhang Youjia, Lei Yuan, Chen Yuhong, Sun Xinghuai
AI Summary
ABCA1 regulates eye pressure by modulating the Cav1/eNOS/NO pathway, and its activation improved outflow facility. This mechanism presents ABCA1 as a novel therapeutic target for glaucoma.
Abstract
Purpose
This study aimed to investigate the role and pathophysiological mechanism of ATP binding cassette transporter A1 (ABCA1) in regulating the IOP and aqueous humor outflow.
Methods
ABCA1 expression was measured in trabecular meshwork samples obtained from patients with POAG and human donor eyes by Western blot. To further evaluate the functional significance of ABCA1, porcine angular aqueous plexus (AAP) cells, which are equivalent to human Schlemm's canal endothelial cells, were either treated with ABCA1 agonist GW3965 or transduced with lentivirus expressing ABCA1-shRNA. Transendothelial electrical resistance, protein expression, and nitric oxide (NO) concentration were measured. GW3965 was administered by intracameral injection. IOP and aqueous humor outflow facility were also measured.
Results
ABCA1 expression was significantly higher in the trabecular meshwork tissue of patients with POAG compared with controls. ABCA1 upregulation in angular aqueous plexus cells decreased the transendothelial electrical resistance in the angular aqueous plexus monolayers accompanied by a 0.56-fold decrease in caveolin-1 expression and a 2.85-fold and 1.17-fold increase in endothelial NO synthase expression and NO concentration, respectively (n = 3, P < 0.05). Conversely, ABCA1 downregulation increased transendothelial electrical resistance and caveolin-1 expression and decreased endothelial NO synthase expression and NO production (n = 3, P < 0.05). GW3965 decreased IOP and significantly increased conventional outflow facility (P < 0.05).
Conclusions
Regulation of aqueous humor outflow via the caveolin-1/endothelial NO synthase/NO pathway is a newly defined function of ABCA1 that is different from its traditional role in mediating cholesterol efflux. ABCA1 is a compelling, novel therapeutic candidate for the treatment of glaucoma and ocular hypertension.
MeSH Terms
Shields Classification
Key Concepts6
ABCA1 expression was significantly higher in the trabecular meshwork tissue of patients with POAG compared with controls, as measured by Western blot.
ABCA1 upregulation in angular aqueous plexus cells decreased the transendothelial electrical resistance in the angular aqueous plexus monolayers, accompanied by a 0.56-fold decrease in caveolin-1 expression and a 2.85-fold and 1.17-fold increase in endothelial NO synthase expression and NO concentration, respectively (n = 3, P < 0.05).
ABCA1 downregulation in angular aqueous plexus cells increased transendothelial electrical resistance and caveolin-1 expression and decreased endothelial NO synthase expression and NO production (n = 3, P < 0.05).
Intracameral injection of GW3965 (ABCA1 agonist) decreased IOP and significantly increased conventional outflow facility (P < 0.05).
Regulation of aqueous humor outflow via the caveolin-1/endothelial NO synthase/NO pathway is a newly defined function of ABCA1, different from its traditional role in mediating cholesterol efflux.
ABCA1 is a compelling, novel therapeutic candidate for the treatment of glaucoma and ocular hypertension.
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