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Younghee Kim, Nagaraj Kerur, Shengjian Li, Ana Bastos-Carvalho, Bradley D Gelfand, William W Hauswirth, Jayakrishna Ambati; Extracellular HMGB1 promotes choroidal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4459.
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© ARVO (1962-2015); The Authors (2016-present)
High mobility group box 1 (HMGB1) protein acts as a cellular alarm against pathologic inflammation and its extracellular release by acetylation has been reported to be required for its angiogenic cytokine function. HMGB1 has been recently suggested as a novel therapeutic target for angiogenesis; however the association between its acetylation and angiogenic function in vivo is not clear. Here we aim to examine HMGB1 effect on choroidal angiogenesis (CNV) and extracellular HMGB1 expression related to its acetylation.
To investigate the effect of HMGB1 on angiogenesis, we used a mouse model of laser coagulation-induced CNV and measured CNV volume by FITC-conjugated GS-IB4 staining after treatment of a neutralizing antibody or recombinant protein of HMGB1 in WT mice. To confirm whether HMGB1 protein expression is related to CNV induction, we examined not only total HMGB1 protein but also extracellular HMGB1 protein and its acetylation in retina and retinal pigment epithelium/choroid (RPE/C) from CNV eyes comparing to WT by Western blotting. In addition, we measured CNV volume by RPE-specific knockdown of HMGB1 by subretinal injection of AAV1-VMD2-Cre to HMGB1f/f mice comparing to control AAV1-VMD2-GFP group.
We confirmed that antibody neutralization of HMGB1 reduced CNV, whereas administration of recombinant HMGB1 protein induced CNV, implying that both endogenous and exogenous HMGB1 promote CNV. In Western blotting, total HMGB1 protein abundance did not change in both retina and RPE/C by laser injury, however extracellular HMGB1 release and its acetylation occurred in retina and RPE/C by laser-induced CNV.
Taken together, these data suggest that extracellular HMGB1 by its acetylation is related to CNV development, and control of HMGB1 expression and localization can be a novel therapeutic target for in vivo angiogenesis.
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