ABCA1 Regulates IOP by Modulating Cav1/eNOS/NO Signaling Pathway

Abstract

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.

Glaucoma Heritability: Molecular Mechanisms of Disease

“…In a 2020 study, Hu et al proposed a pathophysiologic mechanism for the role of ABCA1 in regulating IOP, and an alternate function to its role in cholesterol homeostasis. They suggested that ABCA1 changes Cav1 expression, resulting in a decreased inhibitory influence of Cav1 on eNos, resulting in the increased nitric oxide production by eNOS and, ultimately, reduced IOP (Table 2) [19]. Additionally, they confirmed that ABCA1 had higher expression in the trabecular meshwork of POAG patients versus controls, confirming previous work suggesting the enhanced expression of ABCA1 as a diagnostic marker for glaucoma [19,23].…”

“…Importantly, ABCA1 is regulated by the liver X receptor [41]. While ABCA1 has been implicated in retinal inflammation and retinal ganglion cell apoptosis, recent research has also demonstrated that ABCA1 has a role in regulating IOP through aqueous humor dynamics [19,22]. In a 2020 study, Hu et al proposed a pathophysiologic mechanism for the role of ABCA1 in regulating IOP, and an alternate function to its role in cholesterol homeostasis.…”

“…They suggested that ABCA1 changes Cav1 expression, resulting in a decreased inhibitory influence of Cav1 on eNos, resulting in the increased nitric oxide production by eNOS and, ultimately, reduced IOP (Table 2) [19]. Additionally, they confirmed that ABCA1 had higher expression in the trabecular meshwork of POAG patients versus controls, confirming previous work suggesting the enhanced expression of ABCA1 as a diagnostic marker for glaucoma [19,23]. Therefore, it is possible that variants in ABCA1 and NR1H3 result in altered IOP and aqueous outflow regulation.…”

“…Interestingly, the meta-pathways Springelkamp et al developed singled out pathways associated with abnormal fat cell and liver morphologies, noting that these pathways centered on ABCA1 [59]. As described above, ABCA1 is a transmembrane transporter with a role in cholesterol processing that has recently been linked to IOP regulation and aqueous humor dynamics (Table 3) [19]. So, while this recent development explains the linkage between ABCA1, IOP, and the meta-pathways described by Springelkamp et al, the link to CDR is still unclear.…”

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

“…A recent study reported evidence of a novel role for ABCA1 in IOP modulation via the regulation of the Cav1/eNOS/NO signaling, which is likely to be an important mechanism of pathogenesis in patients with POAG. Based on their findings, the authors suggest that enhancing the ABCA1 signaling pathway could be of therapeutic value in the treatment of glaucoma and ocular hypertension [ 297 ].…”