PRMT5 is a therapeutic target in choroidal neovascularization
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 ide...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-28215-w |
| _version_ | 1811171791807184896 |
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| author | Anbukkarasi Muniyandi Matthew Martin Kamakshi Sishtla Aishat Motolani Mengyao Sun Nathan R. Jensen Xiaoping Qi Michael E. Boulton Lakshmi Prabhu Tao Lu Timothy W. Corson |
| author_facet | Anbukkarasi Muniyandi Matthew Martin Kamakshi Sishtla Aishat Motolani Mengyao Sun Nathan R. Jensen Xiaoping Qi Michael E. Boulton Lakshmi Prabhu Tao Lu Timothy W. Corson |
| author_sort | Anbukkarasi Muniyandi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T17:20:00Z |
| format | Article |
| id | doaj.art-f0a1f78df83048a59d1f98fb75a67cf1 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-10T17:20:00Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-f0a1f78df83048a59d1f98fb75a67cf12023-02-05T12:11:08ZengNature PortfolioScientific Reports2045-23222023-01-0113111810.1038/s41598-023-28215-wPRMT5 is a therapeutic target in choroidal neovascularizationAnbukkarasi Muniyandi0Matthew Martin1Kamakshi Sishtla2Aishat Motolani3Mengyao Sun4Nathan R. Jensen5Xiaoping Qi6Michael E. Boulton7Lakshmi Prabhu8Tao Lu9Timothy W. Corson10Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of MedicineDepartment of Pharmacology & Toxicology, Indiana University School of MedicineDepartment of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of MedicineDepartment of Pharmacology & Toxicology, Indiana University School of MedicineDepartment of Pharmacology & Toxicology, Indiana University School of MedicineDepartment of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of MedicineDepartment of Ophthalmology and Visual Sciences, University of Alabama at BirminghamDepartment of Ophthalmology and Visual Sciences, University of Alabama at BirminghamDepartment of Pharmacology & Toxicology, Indiana University School of MedicineDepartment of Pharmacology & Toxicology, Indiana University School of MedicineDepartment of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of MedicineAbstract 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.https://doi.org/10.1038/s41598-023-28215-w |
| spellingShingle | Anbukkarasi Muniyandi Matthew Martin Kamakshi Sishtla Aishat Motolani Mengyao Sun Nathan R. Jensen Xiaoping Qi Michael E. Boulton Lakshmi Prabhu Tao Lu Timothy W. Corson PRMT5 is a therapeutic target in choroidal neovascularization Scientific Reports |
| title | PRMT5 is a therapeutic target in choroidal neovascularization |
| title_full | PRMT5 is a therapeutic target in choroidal neovascularization |
| title_fullStr | PRMT5 is a therapeutic target in choroidal neovascularization |
| title_full_unstemmed | PRMT5 is a therapeutic target in choroidal neovascularization |
| title_short | PRMT5 is a therapeutic target in choroidal neovascularization |
| title_sort | prmt5 is a therapeutic target in choroidal neovascularization |
| url | https://doi.org/10.1038/s41598-023-28215-w |
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