| Title: |
PRMT5 is a therapeutic target in choroidal neovascularization. |
| Authors: |
Muniyandi, Anbukkarasi, Martin, Matthew, Sishtla, Kamakshi, Motolani, Aishat, Sun, Mengyao, Jensen, Nathan R., Qi, Xiaoping, Boulton, Michael E., Prabhu, Lakshmi, Lu, Tao, Corson, Timothy W. |
| Source: |
Scientific Reports; 1/31/2023, Vol. 13 Issue 1, p1-18, 18p |
| Subject Terms: |
NF-kappa B, MACULAR degeneration, VASCULAR endothelial growth factors, RETINAL ganglion cells, NEOVASCULARIZATION, PROTEIN arginine methyltransferases, ENDOSTATIN, METHYLTRANSFERASES |
| Abstract: |
Ocular neovascular diseases including neovascular age-related macular degeneration (nvAMD) are widespread causes of blindness. Patients' non-responsiveness to currently used biologics that target vascular endothelial growth factor (VEGF) poses an unmet need for novel therapies. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a novel therapeutic target for nvAMD. PRMT5 is a well-known epigenetic enzyme. We previously showed that PRMT5 methylates and activates a proangiogenic and proinflammatory transcription factor, the nuclear factor kappa B (NF-κB), which has a master role in tumor progression, notably in pancreatic ductal adenocarcinoma and colorectal cancer. We identified a potent and specific small molecule inhibitor of PRMT5, PR5-LL-CM01, that dampens the methylation and activation of NF-κB. Here for the first time, we assessed the antiangiogenic activity of PR5-LL-CM01 in ocular cells. Immunostaining of human nvAMD sections revealed that PRMT5 is highly expressed in the retinal pigment epithelium (RPE)/choroid where neovascularization occurs, while mouse eyes with laser induced choroidal neovascularization (L-CNV) showed PRMT5 is overexpressed in the retinal ganglion cell layer and in the RPE/choroid. Importantly, inhibition of PRMT5 by PR5-LL-CM01 or shRNA knockdown of PRMT5 in human retinal endothelial cells (HRECs) and induced pluripotent stem cell (iPSC)-derived choroidal endothelial cells (iCEC2) reduced NF-κB activity and the expression of its target genes, such as tumor necrosis factor α (TNF-α) and VEGF-A. In addition to inhibiting angiogenic properties of proliferation and tube formation, PR5-LL-CM01 blocked cell cycle progression at G1/S-phase in a dose-dependent manner in these cells. Thus, we provide the first evidence that inhibition of PRMT5 impedes angiogenesis in ocular endothelial cells, suggesting PRMT5 as a potential therapeutic target to ameliorate ocular neovascularization. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
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