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Maria Fernanda Suarez, Heather Schmitt, Kristyn Hake, Megan Kuhn, TeddiJo Watkins, Michael H Elliott, Michael A Hauser, Daniel W Stamer; Characterization of Loxl1-knockout-induced elastosis in mice with different genetic backgrounds. Invest. Ophthalmol. Vis. Sci. 2022;63(7):446.
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Pseudoexfoliation syndrome (PEX) is a systemic, age-related disorder characterized by the deposition of fibrillar material in body tissues. Pseudoexfoliation glaucoma (PEXG), the ocular manifestation of PEX, is the most common identifiable secondary form of open angle glaucoma. PEXG is characterized by greater IOP elevation, advanced loss of visual field upon diagnosis, and resistance to IOP therapies. Polymorphisms in lysyl oxidase-like 1 (LOXL1), an enzyme that crosslinks collagen/elastin and is critical for ECM formation and repair, significantly associates with PEX. Since LOXL1 levels appear lower and elastosis higher in people with PEX, the aim of the study was to characterize the ocular and non-ocular elastosis phenotypes associated with Loxl1-/- mice
129S.C57Bl/6 Loxl1+/- mice were backcrossed onto C57Bl/6 or 129S background and aged for 2 months. Early onset and high prevalence of spontaneous anal prolapse in C57Bl/6 background mice necessitated the study of younger animals. Skin elastic recovery measurements, histology and western blots were performed to analyze systemic organ changes. For ocular studies, outflow facility was measured by iPerfusion, Schlemm’s canal (SC) perimeter was quantified using ImageJ in semi thin histology sections, and the presence of extracellular matrix accumulation below inner wall of SC was documented by transmission electron microscopy
Skin elastic recovery was significantly lower in Loxl1-/- N6 C57Bl/6 mice (23.18%) compared to Loxl1-/- from 129S.C57Bl/6 mice (48.67%) (p=0.0015). N6 C57Bl/6 Loxl1-/- mice showed qualitatively enlarged luminal spaces of lung and lax elastin orientation in both systemic and in ocular tissues. Densitometric analysis of western blots from lung tissue displayed increased tropoelastin expression in Loxl1-/- respect to Loxl1+/+ for N6 C57Bl/6 mice (1.56-fold) and for 129S.C57Bl/6 mice (1.50-fold) (p<0.05). No changes were observed in outflow facility for both mice backgrounds, except between Loxl1+/- and Loxl1-/- (2.54 vs 4.48 nl/min/ mmHg) for the mixed background (p= 0.042). By TEM we observed increased ECM accumulation in the SC inner wall in Loxl1+/- and Loxl1-/- mice from both backgrounds
Results show that genetic background significantly influences the elastosis phenotype at both the systemic and ocular levels, providing an opportunity to identify the genes associated with genetic susceptibility
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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