Caveolin-1 Promotes Cellular Senescence in Exchange for Blocking Subretinal Fibrosis in Age-Related Macular Degeneration

Abstract

Purpose To determine whether caveolin-1 (i) prevents epithelial–mesenchymal transition in the RPE and laser-induced subretinal fibrosis and (ii) promotes or inhibits cellular senescence in the RPE. Methods We examined laser-induced subretinal fibrosis and RPE cell contraction in wild-type and Caveolin-1 knockout ( Cav-1 −/− ) mice treated with or without cavtratin, a cell-permeable peptide of caveolin-1. The senescence marker p16 INK4a was measured in RPE tissues from patients with geographic atrophy and aged mice, laser-induced subretinal fibrosis, and primary human RPE cells. Human RPE was examined by TUNEL staining, reactive oxygen species generation, cell viability, and senescence-associated β-galactosidase staining. Results The volume of subretinal fibrosis was significantly smaller in cavtratin-injected eyes from wild-type mice than in control eyes from wild-type, P = 0.0062, and Cav-1 −/− mice, P = 0.0095. Cavtratin treatment produced significant improvements in primary RPE cell contraction in wild-type, P = 0.04, and Cav-1 −/− mice, P = 0.01. p16 INK4a expression in the RPE was higher in patients with than without geographic atrophy. p16 INK4a was expressed in 18-month-old but not 2-month-old wild-type mouse eyes. p16 INK4a and collagen type I antibodies showed co-localization in subretinal fibrosis. Cavtratin did not affect RPE cell apoptosis or reactive oxygen species generation, but decreased cell viability and increased senescence-associated β-galactosidase–positive cells. Conclusions Enhanced expression of caveolin-1 successfully blocked epithelial–mesenchymal transition of RPE and the reduction of subretinal fibrosis in mice. Nevertheless, in exchange for blocking subretinal fibrosis, caveolin-1 promotes RPE cellular senescence and might affect the progression of geographic atrophy in AMD.

Subretinal fibrosis in neovascular age-related macular degeneration: current concepts, therapeutic avenues, and future perspectives

“…No claim to completeness. CNV: choroidal neovascularization, OIR: oxygen induced retinopathy, RPE: retinal pigment epithelium Therapy Model Route of administration Reference Ac-EEED (actin blockage) Mouse, laser CNV intravitreal Caballero et al ( 2011 ) Adrenomedullin Mouse laser CNV intravitreal Tanaka et al ( 2020 ) Cavtratin (caveolin-1) Mouse laser CNV intravitreal Shimizu et al ( 2020 ) Connective tissue growth factor antagonism Rat laser CNV intravitreal Daftarian et al ( 2019 ) Cyclooxygenase 2 antagonism (NS-398) Mouse laser CNV intraperitoneal Zhang et al ( 2016 ) Doxycyclin Mouse laser CNV intraperitoneal Peng et al ( 2018 ) Fibroblast growth factor 2 antagonism (RBM-007) Mouse and rat laser CNV intravitreal Matsuda et al ( 2019 ) Heat shock protein 70 Mouse subretinal fibrosis intravitreal Yang et al ( 2013 ) Interleukin 6 antagonism Mouse subretinal fibrosis intravitreal Sato et al ( 2018b ) Interleukin 6 receptor antagonism Mouse subretinal fibrosis intravitreal Sato et al ( …”

Human umbilical cord mesenchymal stem cell-derived exosomal miR-27b attenuates subretinal fibrosis via suppressing epithelial–mesenchymal transition by targeting HOXC6

“…Several studies explained that anti-VEGFA treatment promoted the formation of fibrotic scars in the subretinal space, and fibrotic changes could reduce the efficacy of the anti-VEGFA pathway [6][7][8]. Therefore, the treatment of progressive fibrosis, including the reversal of EMT and the restoration of the epithelial phenotype, should be potential targets for neovascular AMD-related subretinal fibrosis [9,10].…”

Characterization of a Novel Caveolin Modulator That Reduces Vascular Permeability and Ocular Inflammation

“…29 Key components of the inflammatory process in uveitis include the invasion of the eye by both T cells and macrophages, breakdown of the blood-retinal barrier, edema, and leakage of protein into the aqueous and vitreous. Prior work has shown that AP-Cav reduced the influx of inflammatory cells in an immune models of MS, asthma, and retinal disease [17][18][19]28 and reduced the actions and production of cytokines. 15,30 Therefore, we examined the actions of CVX51401 in the IRBP model of uveitis that has a strong immunological and cytokine component to disease pathogenesis.…”

“…It would be of interest to test CVX51401 in models of retinal and choroidal leakage and neovascularization because AP-Cav was additive with an anti-VEGF antibody in reducing retinal disease and more recently shown to reduce epithelial-mesenchymal transition and laser induced subretinal fibrosis. 28 Uveitis is a collection of conditions causing inflammation of the uveal tract (iris, ciliary body, and choroid) and often involves the retina. Current treatment goals are the suppression of inflammation using steroids in combination with immunomodulators such as methotrexate, mycophenolate mofetil, and biologic modifiers in combination.…”

“…It would be of interest to test CVX51401 in models of retinal and choroidal leakage and neovascularization because AP-Cav was additive with an anti-VEGF antibody in reducing retinal disease and more recently shown to reduce epithelial-mesenchymal transition and laser induced subretinal fibrosis. 28 …”