CD36 Deficiency Leads to Choroidal Involution via COX2 Down-Regulation in Rodents.Reportar como inadecuado

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* Corresponding author 1 Centre de Recherche des Cordeliers 2 Laboratoire de Physiopathologie Cellulaire et Moleculaire de la Retine 3 Institute of Clinical Physiology 4 UPCG - Unité de Pharmacologie Chimique et Génétique 5 Department of Pediatrics, Ophthalmology and Pharmacology 6 Faculty of Pharmacy

Abstract : BACKGROUND: In the Western world, a major cause of blindness is age-related macular degeneration AMD. Recent research in angiogenesis has furthered the understanding of choroidal neovascularization, which occurs in the -wet- form of AMD. In contrast, very little is known about the mechanisms of the predominant -dry- form of AMD, which is characterized by retinal atrophy and choroidal involution. The aim of this study is to elucidate the possible implication of the scavenger receptor CD36 in retinal degeneration and choroidal involution, the cardinal features of the dry form of AMD. METHODS AND FINDINGS: We here show that deficiency of CD36, which participates in outer segment OS phagocytosis by the retinal pigment epithelium RPE in vitro, leads to significant progressive age-related photoreceptor degeneration evaluated histologically at different ages in two rodent models of CD36 invalidation in vivo Spontaneous hypertensive rats SHR and CD36- mice. Furthermore, these animals developed significant age related choroidal involution reflected in a 100%-300% increase in the avascular area of the choriocapillaries measured on vascular corrosion casts of aged animals. We also show that proangiogenic COX2 expression in RPE is stimulated by CD36 activating antibody and that CD36-deficient RPE cells from SHR rats fail to induce COX2 and subsequent vascular endothelial growth factor VEGF expression upon OS or antibody stimulation in vitro. CD36- mice express reduced levels of COX2 and VEGF in vivo, and COX2- mice develop progressive choroidal degeneration similar to what is seen in CD36 deficiency. CONCLUSIONS: CD36 deficiency leads to choroidal involution via COX2 down-regulation in the RPE. These results show a novel molecular mechanism of choroidal degeneration, a key feature of dry AMD. These findings unveil a pathogenic process, to our knowledge previously undescribed, with important implications for the development of new therapies.

Autor: Marianne Houssier - William Raoul - Sophie Lavalette - Nicole Keller - Xavier Guillonneau - Barbara Baragatti - Laurent Jonet - J



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