Journal article
Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury
Scientific reports, Vol.8(1), pp.13387-8
09/06/2018
DOI: 10.1038/s41598-018-31846-z
PMCID: PMC6127142
PMID: 30190604
Abstract
Age-related macular degeneration (AMD) is a common, blinding disease associated with increased complement system activity. Eyes with AMD show elevated accumulation of the membrane attack complex (MAC) in the choriocapillaris and degeneration of macular choriocapillaris endothelial cells (ECs). Thus, one could reasonably conclude that the endothelial cell death that occurs in AMD is due to injury by the MAC. We therefore sought to identify strategies for protecting ECs against MAC lysis. RF/6A endothelial cells were pre-incubated with a library of FDA-approved small molecules, followed by incubation with complement intact human serum quantification of cell death. Two closely related molecules identified in the screen, econazole nitrate and miconazole nitrate, were followed in validation and mechanistic studies. Both compounds reduced lysis of choroidal ECs treated with complement-intact serum, across a range of doses from 1 to 100 µM. Cell rescue was confirmed in mouse primary choroidal ECs. Both exosome release and cell surface roughness (assessed using a Holomonitor system) were reduced by drug pretreatment in RF/6A cells, whereas endosome formation increased with both drugs, consistent with imidazole-mediated alterations of cell surface dynamics. The results in the current study provide further proof of principle that small molecules can protect choroidal ECs from MAC-induced cell death and suggest that FDA approved compounds may be beneficial in reducing vascular loss and progression of AMD.
Details
- Title: Subtitle
- Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury
- Creators
- Shemin Zeng - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USAKuo-Kuang Wen - University of Iowa Department of Biochemistry, Iowa City, USAGrefachew Workalemahu - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USAElliott H Sohn - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USAMeng Wu - University of Iowa Department of Biochemistry, Iowa City, USAKathleen R Chirco - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USAMiles J Flamme-Wiese - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USAXiuying Liu - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USAEdwin M Stone - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USABudd A Tucker - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USARobert F Mullins - University of Iowa Department of Ophthalmology and Visual Sciences, Iowa City, USA. robert-mullins@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.8(1), pp.13387-8
- DOI
- 10.1038/s41598-018-31846-z
- PMID
- 30190604
- PMCID
- PMC6127142
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Publisher
- England
- Grant note
- EY025580 / U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) EY-026547 / U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) Unrestricted grant / Research to Prevent Blindness (RPB) EY-024605 / U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) EY-026547 / U.S. Department of Health & Human Services | NIH | Center for Information Technology (CIT)
- Language
- English
- Date published
- 09/06/2018
- Academic Unit
- Pharmacy; Stead Family Department of Pediatrics; Core Research Facilities; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979981702771
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