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M. Houssier, X. Guillonneau, H. Ong, B. Baragatti, F. Coceani, F. Behar-Cohen, S. Chemtob, F. Sennlaub; Cd36 Deficiency Leads to Choroidal Involution via Cox-2 Downregulation In Rpe. Invest. Ophthalmol. Vis. Sci. 2007;48(13):25.
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© ARVO (1962-2015); The Authors (2016-present)
A cardinal feature of dry AMD is choroidal involution. The molecular mechanisms that lead to choroidal involution remain unclear. CD36 is expressed in RPE cells and is involved in mechanisms of ROS phagocytosis. COX2 is constitutively expressed in RPE cells and is positively regulated by ROS phagocytosis. Interference with mechanisms of RPE phagocytosis could impede RPE COX2 expression and influence choroidal homeostasis.
CD36 and COX2 knockout mice, RCS rats and SHR rats (that express a non-functional CD36) and their control were used. Choriocapillary thickness was measured on vascular corrosion casts and paraffin embedded histological sections. Frozen section were used for CD36, COX2 and VEGF immunochemistry, and Real Time PCR were performed for COX2 and VEGF expression in vivo and in vitro in RPE cells from SHR rats and controls.
CD36 is expressed in RPE cells and in the choriocapillaries. Aged CD36-/- mice and SHR rats present a significant thinning and moth eaten appearance of the choroicapillaries compared to control animals. Real time RT-PCR in SHR rats and immunohistochemistry on SHR rats and CD36-/- animals show a significant decrease (as compared to control) of COX2 and Vegf expression in the RPE, preceeding the choroidal thinning. Moreover aged COX2-/- animals led to a significant thinning of the choroid and diminished signal of VEGF immunohistochemistry in RPE. In vitro, COX2 and VEGF mRNA are induced in rat RPE cells incubated with ROS. This induction is blunted in SHR RPE cells. Inhibition of COX2 with DUP-697 in RPE cell culture decreased the VEGF mRNA induction by ROS.
We show that CD36 invalidation leads to choroidal involution in the rat and in the mouse. Using RPE cells from control and SHR rats, and COX2 selective inhibitors we show that ROS induced COX2 expression in RPE is CD36 dependent and ROS induced RPE VEGF expression is mediated by COX2. The in vivo relevance of this mechanism is supported by the fact that a significant choroidal involution is also observed in Cox-2 -/-.CD36 -/- animals present a progressive choroidal involution with age, a major symptom of dry AMD. In a more general way, we show a new pathological mechanism that links deficient RPE phagocytosis of ROS to choroidal involution by the bias of diminished COX2 and VEGF expression in the RPE. Our data provides evidence that choroidal involution appears secondary to an RPE phagocytosis defect rather than a primary event.
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