Senescence Increases Choroidal Endothelial Stiffness and Susceptibility to Complement Injury: Implications for Choriocapillaris Loss in AMD

Cabrera, Andrea; Bhaskaran, Arun; Xu, Jun; Yang, Xiao; Scott, Harry; Mohideen, U.; Ghosh, Kaustabh

doi:10.1167/iovs.16-19727

Cited by 47 publications

(49 citation statements)

References 57 publications

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“…The possibility that altered membrane dynamics, shown both by decreased surface roughness and increased endosome trafficking in this study, results in differential sensitivity to MAC injury by ECs is consistent with a recent report that membrane stiffness (associated with cellular senescence) contributes to degree of MAC injury 31 . Further studies will be required to determine specific molecular steps involved in this process and how those steps are impacted by imidazole drugs.…”

Section: Discussionsupporting

confidence: 92%

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury

Zeng

Wen

Workalemahu

et al. 2018

Sci Rep

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Age-related macular degeneration (AMD) is a common, blinding disease associated with increased complement system activity. Eyes with AMD show elevated accumulation of the membrane attack complex (MAC) in the choriocapillaris and degeneration of macular choriocapillaris endothelial cells (ECs). Thus, one could reasonably conclude that the endothelial cell death that occurs in AMD is due to injury by the MAC. We therefore sought to identify strategies for protecting ECs against MAC lysis. RF/6A endothelial cells were pre-incubated with a library of FDA-approved small molecules, followed by incubation with complement intact human serum quantification of cell death. Two closely related molecules identified in the screen, econazole nitrate and miconazole nitrate, were followed in validation and mechanistic studies. Both compounds reduced lysis of choroidal ECs treated with complement-intact serum, across a range of doses from 1 to 100 µM. Cell rescue was confirmed in mouse primary choroidal ECs. Both exosome release and cell surface roughness (assessed using a Holomonitor system) were reduced by drug pretreatment in RF/6A cells, whereas endosome formation increased with both drugs, consistent with imidazole-mediated alterations of cell surface dynamics. The results in the current study provide further proof of principle that small molecules can protect choroidal ECs from MAC-induced cell death and suggest that FDA approved compounds may be beneficial in reducing vascular loss and progression of AMD.

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Section: Discussionsupporting

confidence: 92%

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury

Zeng

Wen

Workalemahu

et al. 2018

Sci Rep

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“…28 Alternatively, a primary CC vascular loss, due to complement-mediated damage or other genetic and nongenetic factors, may lead to outer retinal layer dysfunction, with impaired removal of debris from Bruch's membrane and RPE ischemia. [29][30][31] McLeod et al 32 have extensively studied the causative relationship between outer retinal layer disruption and CC impairment. They analyzed the postmortem choroids from 11 subjects, including three age-matched controls, five GA subjects, and three nAMD subjects.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the Choriocapillaris in Intermediate Age-Related Macular Degeneration

Borrelli

Uji

Sarraf

et al. 2017

Invest. Ophthalmol. Vis. Sci.

140

134

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“…Human RPE cell line ARPE-19 was purchased from the American Type Culture Collection (Manassas, VA and Rockville, MD, USA). Monkey chorioretinal vessel endothelial cell (RF/6 A) was obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China) and was identified as being of endothelial origin with cellular morphology, growth pattern, ultrastructure, immunocytochemistry, and immunodiffusion 36 . All cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 μg/mL streptomycin, and 100 U/mL penicillin and maintained at 37 °C in a humidified environment with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Advanced glycation end products promote VEGF expression and thus choroidal neovascularization via Cyr61-PI3K/AKT signaling pathway

Sun

Huang

et al. 2017

Sci Rep

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Choroidal neovascularisation (CNV) causes severe vision loss among old patients, especially those with diabetes. Previously, Cyr61 has been found to play a critical role in the pathogenesis of both AMD and diabetes. In the present study, we found that increased CNV severity together with higher expression of Cyr61 and VEGF in diabetes mice compared with control mice. Moreover, knockdown of Cyr61 decreased CNV severity. In vitro mechanism study revealed that the advanced glycation end products (AGEs) significantly increased the expression of Cyr61 in retinal pigment epithelial (RPE) cells, mimicking the effects of diabetes. In turn, the increased Cyr61 enhanced VEGF expression through FAK and PI3K/Akt pathways. Chemically blocking the above pathway significantly inhibited CNV formation, providing a new strategy for clinical prevention and treatment of CNV in related diseases.

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Senescence Increases Choroidal Endothelial Stiffness and Susceptibility to Complement Injury: Implications for Choriocapillaris Loss in AMD

Cited by 47 publications

References 57 publications

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury

Alterations in the Choriocapillaris in Intermediate Age-Related Macular Degeneration

Advanced glycation end products promote VEGF expression and thus choroidal neovascularization via Cyr61-PI3K/AKT signaling pathway

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