3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina
3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with cytoprotective properties and reduced bleeding risks. We studied the potential use of 3K3A-APC as a multi-target therapeutic option for choroidal neovascularization (CNV), a common cause of vision los...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/13/10642 |
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| author | Yehonatan Weinberger Ivan Budnik Yael Nisgav Dahlia Palevski Gil Ben-David José A. Fernández Shany Nivinsky Margalit Sarina Levy-Mendelovich Gili Kenet Dov Weinberger John H. Griffin Tami Livnat |
| author_facet | Yehonatan Weinberger Ivan Budnik Yael Nisgav Dahlia Palevski Gil Ben-David José A. Fernández Shany Nivinsky Margalit Sarina Levy-Mendelovich Gili Kenet Dov Weinberger John H. Griffin Tami Livnat |
| author_sort | Yehonatan Weinberger |
| collection | DOAJ |
| description | 3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with cytoprotective properties and reduced bleeding risks. We studied the potential use of 3K3A-APC as a multi-target therapeutic option for choroidal neovascularization (CNV), a common cause of vision loss in age-related macular degeneration. CNV was induced by laser photocoagulation in a murine model, and 3K3A-APC was intravitreally injected. The impact of 3K3A-APC treatment on myeloid and microglia cell activation and recruitment and on NLRP3 inflammasome, IL-1β, and VEGF levels was assessed using cryosection, retinal flat-mount immunohistochemistry and vascular imaging. Additionally, we evaluated the use of fluorescein angiography as a surrogate marker for in vivo evaluation of the efficacy of 3K3A-APC treatment against leaking CNV lesions. Our results demonstrated that 3K3A-APC treatment significantly reduced the accumulation and activation of myeloid cells and microglia in the CNV area and decreased the NLRP3 and IL-1β levels at the CNV site and the surrounding retina. Furthermore, 3K3A-APC treatment resulted in leakage regression and CNV growth suppression. These findings indicate that the anti-inflammatory activities of 3K3A-APC contribute to CNV inhibition. Our study suggests the potential use of 3K3A-APC as a novel multi-target treatment for CNV. |
| first_indexed | 2024-03-11T01:40:17Z |
| format | Article |
| id | doaj.art-b3454c17de6e43fd9276416c1ee5569d |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:40:17Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b3454c17de6e43fd9276416c1ee5569d2023-11-18T16:41:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-0124131064210.3390/ijms2413106423K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the RetinaYehonatan Weinberger0Ivan Budnik1Yael Nisgav2Dahlia Palevski3Gil Ben-David4José A. Fernández5Shany Nivinsky Margalit6Sarina Levy-Mendelovich7Gili Kenet8Dov Weinberger9John H. Griffin10Tami Livnat11Rabin Medical Center, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Petah-Tikva 5251108, IsraelDepartment of Internal Medicine, The University of Iowa, Iowa City, IA 52242, USARabin Medical Center, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Petah-Tikva 5251108, IsraelRabin Medical Center, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Petah-Tikva 5251108, IsraelRabin Medical Center, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Petah-Tikva 5251108, IsraelDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USARabin Medical Center, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Petah-Tikva 5251108, IsraelFaculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, IsraelFaculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, IsraelRabin Medical Center, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Petah-Tikva 5251108, IsraelDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USARabin Medical Center, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Center, Petah-Tikva 5251108, Israel3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with cytoprotective properties and reduced bleeding risks. We studied the potential use of 3K3A-APC as a multi-target therapeutic option for choroidal neovascularization (CNV), a common cause of vision loss in age-related macular degeneration. CNV was induced by laser photocoagulation in a murine model, and 3K3A-APC was intravitreally injected. The impact of 3K3A-APC treatment on myeloid and microglia cell activation and recruitment and on NLRP3 inflammasome, IL-1β, and VEGF levels was assessed using cryosection, retinal flat-mount immunohistochemistry and vascular imaging. Additionally, we evaluated the use of fluorescein angiography as a surrogate marker for in vivo evaluation of the efficacy of 3K3A-APC treatment against leaking CNV lesions. Our results demonstrated that 3K3A-APC treatment significantly reduced the accumulation and activation of myeloid cells and microglia in the CNV area and decreased the NLRP3 and IL-1β levels at the CNV site and the surrounding retina. Furthermore, 3K3A-APC treatment resulted in leakage regression and CNV growth suppression. These findings indicate that the anti-inflammatory activities of 3K3A-APC contribute to CNV inhibition. Our study suggests the potential use of 3K3A-APC as a novel multi-target treatment for CNV.https://www.mdpi.com/1422-0067/24/13/10642activated protein Cchoroidal neovascularizationinflammation NLRP3microglia |
| spellingShingle | Yehonatan Weinberger Ivan Budnik Yael Nisgav Dahlia Palevski Gil Ben-David José A. Fernández Shany Nivinsky Margalit Sarina Levy-Mendelovich Gili Kenet Dov Weinberger John H. Griffin Tami Livnat 3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina International Journal of Molecular Sciences activated protein C choroidal neovascularization inflammation NLRP3 microglia |
| title | 3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina |
| title_full | 3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina |
| title_fullStr | 3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina |
| title_full_unstemmed | 3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina |
| title_short | 3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina |
| title_sort | 3k3a activated protein c inhibits choroidal neovascularization growth and leakage and reduces nlrp3 inflammasome il 1β and inflammatory cell accumulation in the retina |
| topic | activated protein C choroidal neovascularization inflammation NLRP3 microglia |
| url | https://www.mdpi.com/1422-0067/24/13/10642 |
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