Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
FASEB J. 2019 Oct;33(10):11194-11209. doi: 10.1096/fj.201900756R. Epub 2019 Jul 11.
Glaucoma is a leading cause of irreversible blindness worldwide. Vascular factors play a substantial role in the pathogenesis of glaucoma. Expressed in the vascular endothelium, cytochrome P450 (CYP) 2J2 is one of the CYP epoxygenases that metabolize arachidonic acid to produce epoxyeicosatrienoic acids and exert pleiotropic protective effects on the vasculature. In the present study, we investigated whether endothelium-specific overexpression of CYP2J2 (tie2-CYP2J2-Tr) protects against retinal ganglion cell (RGC) loss induced by glaucoma and in what way retinal vessels are involved in this process. We used a glaucoma model of retinal ischemia-reperfusion (I/R) injury in rats and found that endothelium-specific overexpression of CYP2J2 attenuated RGC loss induced by retinal I/R. Moreover, retinal I/R triggered retinal vascular senescence, indicated by up-regulated senescence-related proteins p53, p16, and β-galactosidase activity. The senescent endothelial cells resulted in pericyte loss and increased endothelial secretion of matrix metallopeptidase 9, which further contributed to RGC loss. CYP2J2 overexpression alleviated vascular senescence, pericyte loss, and matrix metallopeptidase 9 secretion. CYP2J2 suppressed endothelial senescence by down-regulating senescence-associated proteins p53 and p16. These 2 proteins were positively regulated by microRNA-128-3p, which was inhibited by CYP2J2. These results suggest that CYP2J2 protects against endothelial senescence and RGC loss in glaucoma, a discovery that may lead to the development of a potential treatment strategy for glaucoma.-Huang, J., Zhao, Q., Li, M., Duan, Q., Zhao, Y., Zhang, H. The effects of endothelium-specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model.
青光眼是全球范围内导致不可逆性失明的主要原因。血管因素在青光眼的发病机制中起着重要作用。细胞色素 P450（CYP）2J2 在血管内皮细胞中表达，是将花生四烯酸代谢为环氧二十碳三烯酸的 CYP 环氧合酶之一，对血管发挥多种保护作用。在本研究中，我们研究了内皮细胞特异性过表达 CYP2J2（tie2-CYP2J2-Tr）是否可以预防青光眼引起的视网膜神经节细胞（RGC）损失，以及视网膜血管在这个过程中是如何参与的。我们使用了大鼠视网膜缺血再灌注（I/R）损伤的青光眼模型，发现内皮细胞特异性过表达 CYP2J2 可减轻视网膜 I/R 引起的 RGC 损失。此外，视网膜 I/R 引发了视网膜血管衰老，表现为衰老相关蛋白 p53、p16 和β-半乳糖苷酶活性的上调。衰老的内皮细胞导致周细胞丢失和内皮细胞基质金属蛋白酶 9 的分泌增加，这进一步导致 RGC 损失。CYP2J2 过表达减轻了血管衰老、周细胞丢失和基质金属蛋白酶 9 的分泌。CYP2J2 通过下调衰老相关蛋白 p53 和 p16 抑制内皮细胞衰老。这 2 种蛋白受 microRNA-128-3p 的正向调节，而 microRNA-128-3p 受到 CYP2J2 的抑制。这些结果表明，CYP2J2 可预防青光眼内皮细胞衰老和 RGC 损失，这一发现可能为青光眼的治疗策略提供新的思路。
