Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear. METHODS: Recombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis. RESULTS: Here, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924). CONCLUSIONS: ARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch's membrane, ARMS2 protein deficiency due to the genetic risk variant might be involved in drusen formation.

Regular exercise training prevents aortic valve disease in low-density lipoprotein-receptor-deficient mice.

BACKGROUND: Regular exercise training (ET) slows the progression of atherosclerotic lesions, reduces oxidative stress, and increases nitric oxide bioavailability, all of which may be expected to improve degenerative aortic valve disease. METHODS AND RESULTS: Four-week-old low-density lipoprotein-receptor-deficient mice (n=94) were randomly divided into 4 groups: Group 1 (control group), normal diet plus sedentary activity; group 2 (cholesterol group), cholesterol diet plus sedentary activity; group 3 (regular ET group), cholesterol diet plus regular ET (60 min/day, 5 days/week) for 16 weeks; and group 4 (occasional exercise group), cholesterol diet plus occasional ET (1 day/week) for 16 weeks. At 20 weeks of age, histological analysis was performed. A significant increase in aortic valve thickness was evident in the cholesterol group compared with the control group. Importantly, regular but not occasional ET significantly reduced aortic valve thickness compared with the cholesterol group (control 31.3+/-3.0 mum, cholesterol 50.1+/-3.4 mum, regular exercise 30.4+/-1.2 mum, and occasional exercise 48.9+/-3.2 mum). Immunohistochemistry revealed that a cholesterol diet disrupted and regular ET preserved endothelial integrity on the aortic valve surface. Furthermore, serum myeloperoxidase, accumulation of macrophages and oxidized low-density lipoprotein, in situ superoxide, activated myofibroblasts/osteoblast phenotypes, and mineralization were increased in the cholesterol group but were decreased by regular ET. Polymerase chain reaction revealed increased messenger RNA expression for alpha-smooth muscle actin, bone morphogenetic protein-2, runt-related transcription factor-2, and alkaline phosphatase in the cholesterol group, whereas these were diminished by regular ET. Moreover, regular ET significantly increased circulating levels of fetuin-A compared with the cholesterol group. CONCLUSIONS: In the low-density lipoprotein-receptor-deficient mouse, regular ET prevents aortic valve sclerosis by numerous mechanisms, including preservation of endothelial integrity, reduction in inflammation and oxidative stress, and inhibition of the osteogenic pathway.

Secondary glaucoma in uveitis: comparison of the optic nerve head morphology among a nonmydriatic fundus camera, HRT, and SD-OCT.

PURPOSE: To assess the correlation between the disc damage likelihood scale (DDLS) objectively measured by a nonmydriatic fundus camera, confocal laser scanning ophthalmoscopy (HRT3), and spectral-domain optical coherence tomography (SD-OCT) in uveitic glaucoma. METHODS: A total of 59 patients with uveitic glaucoma (21 female, 38 male; mean age 56.8 ± 18.7 years) were included in this prospective cross-sectional study. All patients were measured by the Kowa Nonmyd WX 3D camera (2D/3D nonmydriatic retinal camera, Kowa Company), the HRT3 (Heidelberg Engineering), and SD-OCT (Carl Zeiss Meditec) by one examiner on the same day. All 3 devices graded the optic disc topography. Statistical data were calculated using SPSS (v 20.0, SPSS). RESULTS: In patients showing borderline results in one of the modalities (n = 45), the DDLS showed a significant correlation with the retinal nerve fiber layer (p = 0.016), while Moorfields regression analysis (p = 0.550) and glaucoma probability score (p = 0.629) did not correlate significantly. The highest predictive power was demonstrated by the objectively measured DDLS (area under the receiver operating characteristic curve 0.445-0.588), compared to R. Burk (0.149-0.375) and F.S. Mikelberg (0.033-0.450) coefficients considering HRT and optical coherence tomography. CONCLUSIONS: In this study cohort, the objective DDLS showed the highest predictive power and thus is a reliable tool in diagnosing uveitic glaucoma. These 3 devices cannot be used interchangeably. As diagnosis and follow-ups are challenging in uveitis patients, the stereophotography is additionally a valuable tool.