Purchase this article with an account.
Mao Nakayama, Daisuke Iejima, Masakazu Akahori, Takeshi Iwata; Overexpression of HtrA1 and Smoking Evokes Choroidal Neovascularization and Retinal Deposit in Aged Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6174.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Previous studies have shown that Complement Factor H (CFH) and ARMS2/HtrA1 genes significantly associate with age-related macular degeneration (AMD). In our study, stronger association with ARMS2/HtrA1 compared to CFH in Japanese wet AMD was observed (Goto, Akahori et al., JOBDI 2009). Based on the original report that HtrA1 transcription is elevated in AMD patient (Dewan et al., Science 2005), we generated HtrA1 transgenic mouse (Tg) and observed fundus changes by fluorescein angiography (FA), indocyanine green angiography (IA), optical coherence tomography (OCT) and pathological changes at over 12 month after birth. We also examined the effects of cigarette smoke for these Tg mice to evaluate the progression of the disease by environmental risk factor.
Chicken actin promoter (CAG) was used to drive human HtrA1 expression in entire mouse body and maintained for one year. Fundus observation including FA (Micron III, Phoenix Research), IA and OCT (Spetralis HRA+OCT, Heidelberg Engineering) was performed. The eyes were embedded and sectioned for H&E staining and immunohistochemistry. Smoking exposure to mice was performed using Natural American Spirit cigarette and smoking chamber (INH06-CIGR02A, MIPS). The Tg and control mice were exposed to smoking for 30 min/day and 5 days/week for 12 weeks. After 12 weeks, fundus photo and pathological analysis were performed.
HtrA1 Tg mice at 12 month exhibited hyperfluorescent lesion on FA and low fluorescent on IA. In this lesion choroidal neovascularization (CNV) was observed by OCT. CNV was observed in radial formation spreading from choroid through the RPE into the retina. Immunohistochemistry of CD31/CD34, an endothelial cells marker, and fibronectin, a proliferation marker, were positive in this region. No change was observed for control mice. Our result showed that approximately 18.8% of HtrA1 Tg mice appeared retinal disorders such as CNV. Smoking exposure for three month enhanced CNV by approximately 7.7% for control and 30.0% for Tg mice. In addition, abnormal deposit was observed between photoreceptor and retinal pigment epithelium exclusively for Tg mice exposed to smoking.
Overexpression of HtrA1 in mice induced CNV in mice. Exposure to smoking enhance CNV rate in Tg mice and also in control mice. Our result suggests overexpression of HtrA1 alone can evoke CNV and smoking as strong risk factor for wet AMD.
This PDF is available to Subscribers Only