Abstract
Purpose :
Identification of novel neuroprotective targets for new glaucoma therapies is urgently needed to stop vision loss in patients with glaucoma. One protein potentially involved in glaucoma pathogenesis is proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 is best-known for its actions in liver as a regulator of cholesterol homeostasis, PCSK9 is emerging in the central nervous system as an important protein upregulated in association with neuronal injury and apoptosis. The current understanding of PCSK9 function in retina is limited. We hypothesize that PCSK9 protein is elevated in retinas of ocular hypertensive (OHT) rat eyes.
Methods :
The rat microbead model of glaucoma was used to induce elevated intraocular pressure (IOP) in 8 Brown Norway rats (age 3-9 months). Five weeks post intraocular microbead injection, rats were sacrificed and optic nerves (ONs), retinas or whole eyes were harvested for quantification of axon numbers and for expression of PCSK9 and GFAP proteins by Western blotting and immunohistochemistry (IHC). PCSK9 protein expression was also evaluated in cell lysates from primary mouse Muller cells (MCs) treated with H2O2 (0, 50, 100, 150, 200, and 250 µM) induced oxidative stress for 24 hours.
Results :
After 5 weeks of OHT, PCSK9 and GFAP protein expression were significantly elevated in lysates from OHT compared to contralateral control retinas (** P < 0.01, n=3-4 rats). IHC of frozen retinal sections showed significant elevation of PCSK9 and GFAP in OHT compared to contralateral control retinas (* P < 0.05, n = 3). PCSK9 and GFAP co-localized in Muller cells of the OHT retinas. Cell lysates from primary mouse MCs showed increasing PCSK9 protein with increasing H2O2 concentration up to 150 µM where the PCSK9 increase compared to vehicle treated controls was significant (**P<0.01, n=3 from 2 independent MC isolations).
Conclusions :
The increased PCSK9 protein expression in retinas of OHT eyes and MCs exposed to oxidative stresss support a potential role for PCSK9 in glaucoma pathogenesis and is worthy of further study. This result raises the intriguing possibility that PCSK9 inhibitors currently approved for lowering cholesterol in humans could also be beneficial for glaucoma patients.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.