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Nethrajeith Srinivasalu, Sen Zhang, Yang Hu, Xiangtian Zhou, Jia Qu; Crosstalk between prostanoid receptor (EP2) and peroxisome proliferator-activated receptor (PPAR)-linked cyclic adenosine monophosphate (cAMP) signaling affects myopia in guinea pigs. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3151. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Modulation of EP2 and PPAR affects cAMP levels in various tissue systems. These changes lead to hypoxia and extensive extracellular matrix (ECM) remodeling. While such processes are implicated in myopia development, we aimed to determine if an EP2-mediated crosstalk contributes to the signaling events mediating myopic scleral ECM remodeling.
Three-week old guinea pigs (n=20 in each group) were monocularly injected with an EP2 antagonist (AH6809-10µM/30µM) or a vehicle solution of 0.1% dimethyl sulfoxide (DMSO) for 2 weeks. Few animals underwent form-deprivation (FD) alone, while others also received either 10µM/30µM AH6809 or vehicle injections (FD+DMSO) for 2 weeks. A separate set of animals served as untreated age-matched (AM) controls. Refraction and axial length were measured at 2 weeks, followed by scleral tissue isolation, total RNA extraction (n=10) and gene expression analysis using quantitative polymerase chain reaction. The remaining sclerae underwent radioimmunoassay to detect cAMP levels using a gamma scintillation counter. Statistical significance was estimated using one-way ANOVA with Bonferroni correction (refraction and axial length) and t-tests (cAMP and gene expression levels).
Both FD and FD+DMSO groups developed significant myopia relative to fellow and AM controls. A low dose of AH6809 was adequate to inhibit the progression of experimental myopia (p<0.001), while the highest dose reduced myopic axial elongation (p<0.05). Increase in cAMP levels in FD+DMSO eyes was inhibited by AH6809 (FD+AH6809) injections during FD (p<0.05). The drug had no effect on refraction and axial length under an unobstructed visual environment. Out of a diverse set of 27 genes from PPAR/RXR, cAMP and HIF signaling pathways, 16 were differentially regulated during myopia relative to fellow eyes. However, AH6809 injections during FD either suppressed or completely negated such changes in 15 genes.
EP2 antagonism limits myopia progression by suppressing the increases in scleral cAMP levels, which is accompanied by differential regulation of various downstream genes in the PPAR and HIF signaling pathways. These effects implicate a potential EP2-mediated crosstalk between cAMP, PPAR and HIF signaling pathways may be critical in scleral ECM remodeling and myopia development in guinea pigs.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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