ABCA1 Regulates IOP by Modulating Cav1/eNOS/NO Signaling Pathway
ABCA1 Regulates IOP by Modulating Cav1/eNOS/NO Signaling Pathway
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ABCA1 通过调节 Cav1/eNOS/NO 信号通路调节 IOP
DOI：
10.1167/iovs.61.5.33
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发表时间：
2020-05-01
影响因子：
4.4
通讯作者：
Sun, Xinghuai
中科院分区：
文献类型：
--
作者：
Hu, Chunchun;Niu, Liangliang;Sun, Xinghuai
目的。本研究旨在探讨ATP结合盒转运体A1（ABCA1）在调节眼压（IOP）和房水流出方面的作用及病理生理机制。
方法。通过蛋白质印迹法检测原发性开角型青光眼（POAG）患者和人类供体眼的小梁网样本中ABCA1的表达。为进一步评估ABCA1的功能意义，用ABCA1激动剂GW3965处理猪角房水丛（AAP）细胞（等同于人类施莱姆管内皮细胞），或用表达ABCA1 - 短发夹RNA（shRNA）的慢病毒转导这些细胞。测量跨内皮电阻、蛋白质表达和一氧化氮（NO）浓度。GW3965通过前房内注射给药。还测量了眼压和房水流出易度。
结果。与对照组相比，原发性开角型青光眼患者小梁网组织中ABCA1的表达显著更高。角房水丛细胞中ABCA1的上调降低了角房水丛单层细胞的跨内皮电阻，同时伴有小窝蛋白 - 1表达降低0.56倍，内皮型一氧化氮合酶表达和一氧化氮浓度分别增加2.85倍和1.17倍（n = 3，P < 0.05）。相反，ABCA1的下调增加了跨内皮电阻和小窝蛋白 - 1的表达，降低了内皮型一氧化氮合酶的表达和一氧化氮的产生（n = 3，P < 0.05）。GW3965降低了眼压，并显著增加了常规房水流出易度（P < 0.05）。
结论。通过小窝蛋白 - 1/内皮型一氧化氮合酶/一氧化氮途径调节房水流出是ABCA1一种新定义的功能，不同于其在介导胆固醇流出方面的传统作用。ABCA1是治疗青光眼和高眼压症一种令人瞩目的新型治疗候选物。
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.