Evaluation of Choroidal Structure in Type 1 Macular Neovascularization Using Different Optical Coherence Tomography Analyses: Scale Bar and Binarization.

BACKGROUND: Macular neovascularization (MNV) has been evaluated by optical coherence tomography (OCT) imaging using various approaches. However, few studies have examined their differences. This study analyzed type 1 MNV with a combination of two approaches: scale bar and binarization. METHODS: We enrolled 84 patients with untreated type 1 MNV. We measured choroidal parameters using a scale bar and defined the ratios of superficial choroidal thickness to choroidal vessel diameter (SV ratios). We also used binarization and calculated the ratios of the luminal to the choroidal area (LC ratios) in two directions (horizontal and vertical). RESULTS: Fifty-one patients (61%) were classified as having polyps. SV ratios in the group with polyps were significantly lower than in the group without (p < 0.001). The receiver operating characteristic (ROC) curve showed that the SV ratio was predictive of polyps (AUC 0.733, 95% CI: 0.621-0.844). In patients without polyps, horizontal LC ratios were significantly higher in a subgroup with subretinal fluid than in those without (p = 0.047). The ROC curve showed that the LC ratio was predictive of subretinal fluid (AUC 0.722, 95% CI: 0.517-0.926). CONCLUSION: The SV ratio reflects the MNV disease type, whereas the LC ratio reflects MNV disease activity. Establishing cut-off values for each ratio may be useful for MNV diagnosis.

A synthetic retinoic acid receptor γ antagonist (7C)-loaded nanoparticle enhances bone morphogenetic protein-induced bone regeneration in a rat spinal fusion model.

BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) have potent osteoinductivity and have been applied clinically for challenging musculoskeletal conditions. However, the supraphysiological doses of BMPs used in clinical settings cause various side effects that prevent widespread use, and therefore the BMP dosage needs to be reduced. PURPOSE: To address this problem, we synthesized 7C, a retinoic acid receptor γ antagonist-loaded nanoparticle (NP), and investigated its potential application in BMP-based bone regeneration therapy using a rat spinal fusion model. STUDY DESIGN: An experimental animal study. METHODS: Fifty-three male 8-week-old Sprague-Dawley rats underwent posterolateral spinal fusion and were divided into the following five treatment groups: (1) no recombinant human (rh)BMP-2 and blank-NP (Control), (2) no rhBMP-2 and 1 µg 7C-NP (7C group), (3) low-dose rhBMP-2 (0.5 µg) and 1 µg blank-NP (L-BMP group), (4) low-dose rhBMP-2 (0.5 µg) and 1 µg 7C-NP (L-BMP + 7C group), and (5) high-dose rhBMP-2 (5.0 µg) and 1 µg blank-NP (H-BMP group). Micro-computed tomography and histologic analysis were performed 2 and 6 weeks after the surgery. RESULTS: The spinal fusion rates of the Control and 7C groups were both 0%, and those of the L-BMP, L-BMP + 7C, and H-BMP groups were 55.6%, 94.4%, and 100%, respectively. The L-BMP + 7C group markedly promoted cartilaginous tissue formation during BMP-induced endochondral bone formation that resulted in a significantly better spinal fusion rate and bone formation than in the L-BMP group. Although spinal fusion was slower in the L-BMP + 7C group, the L-BMP + 7C group formed a spinal fusion mass with better bone quality than the spinal fusion mass in the H-BMP group. CONCLUSIONS: The combined use of 7C-NP with rhBMP-2 in a rat posterolateral lumbar fusion model increased spinal fusion rate and new bone volume without deteriorating the quality of newly formed bone. CLINICAL SIGNIFICANCE: 7C-NP potentiates BMP-2-induced bone regeneration and has the potential for efficient bone regeneration with low-dose BMP-2, which can reduce the dose-dependent side effects of BMP-2 in clinical settings.

Cytomegalovirus Retinitis in a Patient Taking Upadacitinib: A Case Report.

Upadacitinib is a relatively new drug used to treat autoimmune diseases. However, patients treated with upadacitinib may develop infections. We report a case of cytomegalovirus (CMV) retinitis that developed during upadacitinib administration. A 79-year-old woman presented with progressively decreasing vision in both eyes. Her decimal best-corrected visual acuity (BCVA) was 0.2 in the right and 0.01 in the left eye. The patient was taking upadacitinib for one year. Fundus examination revealed vitreous opacities and extensive white retinal lesions with hemorrhage in both eyes. CMV was detected in the anterior aqueous humor, vitreous humor, and blood samples. We diagnosed her with panuveitis and CMV retinitis, performed a vitrectomy in both eyes, and administered intravenous ganciclovir and steroids. After treatment, her BCVA improved to 0.6 in the right and 0.1 in the left eye. Ophthalmologists and physicians should be aware of CMV infections in patients being treated with upadacitinib.

En-Face Optical Coherence Tomography Is Useful for Assessing Striated Lesions in Angioid Streaks: A Case Report.

Angioid streaks are mainly characterized by radially striated lesions around the optical disc and result in severe vision loss when choroidal neovascularization (CNV) develops at the macula. The prediction of visual prognosis in cases with angioid streaks remains an unsolved problem. In this study, we report the usefulness of en-face optical coherence tomography (OCT) to assess the bilateral striated lesions in angioid streaks. A 59-year-old female who was previously diagnosed with angioid streaks complained of decreased visual acuity in her left eye. However, on en-face OCT, the striated lesions in the right eye with better vision were shown as thicker continuous lesions than those in the left eye. Twenty-four months after the initial visit, her right visual acuity was worse than her left. En-face OCT showed fine-striated lesions extending from those thicker lesions to the macular area in the right eye. The thicker striated lesions observed at the initial visit may be a risk factor for future CNV development and vision loss. The evaluation of lesion size using en-face OCT may be useful for predicting the visual prognosis in angioid streaks.

Development of an Eccentric Macular Hole Followed by Reopening of the Original Macular Hole as a Long-term Sequelae of Internal Limiting Membrane Peeling and Focal Laser Photocoagulation: A Case Report.

A macular hole (MH) is a widely known disease among ophthalmologists. Vitrectomy with internal limiting membrane (ILM) peeling is a standard technique for full-thickness MHs. However, the recurrence of MHs is sometimes seen. In addition, an eccentric MH is known to rarely occur after vitrectomy. An eccentric MH has been considered to require no therapeutic intervention because of its lack of increase in size. This study reports a case of two MHs (a recurrent MH and an enlarged eccentric MH) developed after laser photocoagulation around the injured retina caused by ILM peeling at the initial surgery. A 56-year-old woman presented with an idiopathic MH in her left eye and best-corrected visual acuity (BCVA) was decreased to 20/80. She underwent phacoemulsification and vitrectomy combined with posterior hyaloid removal, ILM peeling, and 20% sulfur hexafluoride gas tamponade.  During the ILM peeling, we performed laser photocoagulation around the injured retina within the arcade. The MH was successfully closed and her BCVA was improved to 20/20 one month after surgery. Eight months after surgery, an eccentric MH occurred next to the photocoagulation spots. However, her BCVA remained 20/20; thus, we just followed up on her eye. Six years after surgery, her BCVA was decreased to 20/200. The eccentric MH increased in size and the original MH re-opened. The second vitrectomy was performed, but ILM had been already peeled within the arcade during the previous surgery and a usable sufficient size of ILM which could be auto-transplanted to the holes was not obtained. Thus, free flaps of the posterior lens capsule were harvested and placed within each hole. Two holes were successfully closed and her BCVA improved to 10/20 at three months after the surgery. Laser photocoagulation around the injured retina derived from ILM peeling may be a risk for recurrent MHs. .

Review of Basic Research about Ossification of the Spinal Ligaments Focusing on Animal Models.

Ossification of the posterior longitudinal ligament (OPLL) is a heterotopic ossification that may cause spinal cord compression. With the recent development of computed tomography (CT) imaging, it is known that patients with OPLL often have complications related to ossification of other spinal ligaments, and OPLL is now considered part of ossification of the spinal ligaments (OSL). OSL is known to be a multifactorial disease with associated genetic and environmental factors, but its pathophysiology has not been clearly elucidated. To elucidate the pathophysiology of OSL and develop novel therapeutic strategies, clinically relevant and validated animal models are needed. In this review, we focus on animal models that have been reported to date and discuss their pathophysiology and clinical relevance. The purpose of this review is to summarize the usefulness and problems of existing animal models and to help further the development of basic research on OSL.

Sarcoidosis presenting as optic neuritis with vision loss.

Neurosarcoidosis is a rare complication of sarcoidosis and unusually presents as optic neuritis. We present the case of a 51-year-old man who complained of right vision loss. Brain magnetic resonance imaging showed asymmetrical enlargement of the right optic nerve. Chest computed tomography detected mediastinal and hilar lymphadenopathy. There were cutaneous nodules on the back. Biopsy of the mediastinal lymph node by endobronchial ultrasound-guided transbronchial needle aspiration and the skin showed noncaseating granulomas consistent with sarcoidosis. Serum angiotensin-converting enzyme level was elevated (34.2 IU/L) (normal: 8.3-21.4 IU/L). Based on these findings, he was diagnosed as neurosarcoidosis with optic neuritis. He was started on 1000-mg/day methylprednisolone intravenously for 3 days, followed by oral 50-mg/day prednisolone, which was gradually tapered for 8 weeks. Thereafter, the skin nodules and lymphadenopathy decreased and the right vision partially improved. Based on this rare case, sarcoidosis should be considered as a differential diagnosis in cases of optic neuritis.

Alteration of plasma von Willebrand factor in the treatment of retinal vein occlusion with cystoid macular edema.

Retinal vein occlusion (RVO) is a major retinal disease caused by venous thrombosis. Although several studies have proposed an association between venous thrombosis and von Willebrand factor (VWF), the association between RVO and VWF remains unclear. We aimed to investigate the association between RVO and VWF and the alteration of VWF levels under anti-vascular endothelial growth factor (VEGF) treatment. We enrolled 55 patients with RVO involved cystoid macular edema. They received intravitreal injection of anti-VEGF drugs, either ranibizumab or aflibercept. We examined the clinical data and measured plasma VWF antigen and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity to identify variabilities during treatment. At baseline, there was no significant difference between the RVO group and age-matched controls in both VWF antigen and ADAMTS13 activity levels, but ADAMTS13 activity was significantly lower in central RVO than in branch RVO (P = 0.015). In branch RVO, VWF antigen was negatively correlated with central choroidal thickness (r = -0.51, P < 0.001). In branch RVO after anti-VEGF treatment, VWF antigen levels decreased significantly from 134% at baseline to 109% at 1 day (P = 0.002) and 107% at 1 month (P = 0.030) after treatment. In contrast, ADAMTS13 activity showed no significant difference during this period. In branch RVO at 1 month after treatment, VWF antigen was negatively correlated with central choroidal thickness (r = -0.47, P = 0.001). Our findings suggest an association between VWF and central choroidal thickness in patients with branch RVO, thus the measurement of VWF may be useful for evaluating disease activity and prognosis.

Effects of rhBMP-2-loaded hydroxyapatite granules/beta-tricalcium phosphate hydrogel (HA/ß-TCP/hydrogel) composite on a rat model of caudal intervertebral fusion.

The effects and inflammation-related side effects of bone morphogenetic protein (BMP)-2 on posterior lumbar interbody fusion are controversial. One of the potential causes for the inconsistent results is the uncontrolled release of BMP-2 from the collagen carrier. Therefore, BMP delivery systems that support effective bone regeneration while attenuating the side effects are strongly sought for. We developed NOVOSIS putty (NP), a novel composite material of hydroxyapatite (HA), beta-tricalcium phosphate (ß-TCP)/hydrogel, and BMP-2, which can sustainably release BMP-2 over 2 weeks. This study was aimed at comparing the effects and side effects of NP and collagen sponge (CS) containing BMP-2 using a rat caudal intervertebral fusion model. The fusion rates of NP with low and high doses of BMP-2 were significantly higher than those of an iliac bone (IB) graft, but those of CS with low and high doses of BMP-2 were not different from those of the IB graft. Furthermore, the incidences of ectopic bone formation and soft tissue swelling were significantly lower in the NP group than in the CS group. The HA/ß-TCP/hydrogel carrier enabled superior bone induction with low-dose BMP-2 and decreased the incidence of side effects caused by high-dose BMP-2 vis-à-vis the collagen carrier.

Prostaglandin EP4 Selective Agonist AKDS001 Enhances New Bone Formation by Minimodeling in a Rat Heterotopic Xenograft Model of Human Bone.

To enhance bone regeneration, the use of bone morphogenetic protein (BMP)-2 is an attractive option. Unfortunately, the dose-dependent side effects prevent its widespread use. Therefore, a novel osteogenic agent using a different mechanism of action than BMP-2 is highly desirable. Previous reports demonstrated that prostaglandin E2 receptor 4 (EP4) agonists have potent osteogenic effects on non-human cells and are one of the potential alternatives for BMP-2. Here, we investigated the effects of an EP4 agonist (AKDS001) on human cells with a rat heterotopic xenograft model of human bone. Bone formation in the xenograft model was significantly enhanced by AKDS001 treatment. Histomorphometric analysis showed that the mode of bone formation by AKDS001 was minimodeling rather than remodeling. In cultured human mesenchymal stem cells, AKDS001 enhanced osteogenic differentiation and mineralization via the cAMP/PKA pathway. In cultured human preosteoclasts, AKDS001 suppressed bone resorption by inhibiting differentiation into mature osteoclasts. Thus, we conclude that AKDS001 can enhance bone formation in grafted autogenous bone by minimodeling while maintaining the volume of grafted bone. The combined use of an EP4 agonist and autogenous bone grafting may be a novel treatment option to enhance bone regeneration. However, we should be careful in interpreting the results because male xenografts were implanted in male rats in the present study. It remains to be seen whether females can benefit from the positive effects of AKDS001 MS by using female xenografts implanted in female rats in clinically relevant animal models.

Selective Retinoic Acid Receptor γ Antagonist 7C is a Potent Enhancer of BMP-Induced Ectopic Endochondral Bone Formation.

Bone morphogenetic proteins (BMPs) have been clinically applied for induction of bone formation in musculoskeletal disorders such as critical-sized bone defects, nonunions, and spinal fusion surgeries. However, the use of supraphysiological doses of BMP caused adverse events, which were sometimes life-threatening. Therefore, safer treatment strategies for bone regeneration have been sought for decades. Systemic administration of a potent selective antagonist of retinoic acid nuclear receptor gamma (RARγ) (7C) stimulated BMP-induced ectopic bone formation. In this study, we developed 7C-loaded poly lactic nanoparticles (7C-NPs) and examined whether local application of 7C enhances BMP-induced bone regeneration. The collagen sponge discs that absorbed recombinant human (rh) BMP-2 were implanted into the dorsal fascia of young adult mice to induce ectopic bone. The combination of rhBMP-2 and 7C-NP markedly increased the total bone volume and thickness of the bone shell of the ectopic bone in a dose-dependent manner compared to those with rhBMP-2 only. 7C stimulated sulfated proteoglycan production, expression of chondrogenic marker genes, and Sox9 reporter activity in both chondrogenic cells and MSCs. The findings suggest that selective RARγ antagonist 7C or the related compounds potentiate the bone inductive ability of rhBMP-2, as well as support any future research to improve the BMP-2 based bone regeneration procedures in a safe and efficient manner.

Background Factors Affecting Visual Acuity at Initial Visit in Eyes with Central Retinal Vein Occlusion: Multicenter Study in Japan.

PURPOSE: To determine the baseline characteristics of patients with central retinal vein occlusion (CRVO) that were significantly associated with the best-corrected visual acuity (BCVA) at the initial examination. METHODS: This was a retrospective multicenter study using the medical records registered in 17 ophthalmological institutions in Japan. Patients with untreated CRVO (≥20-years-of-age) who were initially examined between January 2013 and December 2017 were studied. The patients' baseline factors that were significantly associated with the BCVA at the initial examination were determined by univariate and multivariate linear regression analyses. RESULTS: Data from 517 eyes of 517 patients were analyzed. Univariate analyses showed that an older age (r = 0.194, p < 0.001) and the right eye (r = -0.103, p < 0.019) were significantly associated with poorer BCVA at the initial visit. Multivariate analyses also showed that an older age (ß = 0.191, p < 0.001) and the right eye (ß = -0.089, p = 0.041) were significantly associated with poorer BCVA at the initial visit. CONCLUSIONS: The results indicate that an older age, a known strong factor, and the right eye were significantly associated with poorer BCVA at the initial visit to the hospital. These results suggest that functional and/or anatomical differences between the right and left eyes may be involved in these results.

Analysis focusing on plasma von Willebrand factor in pachychoroid neovasculopathy and age-related macular degeneration.

Pachychoroid neovasculopathy (PNV) is a new concept of macular disorder. Some cases diagnosed as age-related macular degeneration (AMD) have been re-diagnosed as PNV. However, the biological features of PNV are still uncertain. The purpose of this study was to compare PNV and AMD by analyses focusing on von Willebrand factor (VWF) and complement factor H (CFH). Ninety-seven patients who were previously diagnosed with treatment naïve AMD were enrolled in this study. They were re-classified as either PNV or AMD based on the clinical criteria and 33 patients were classified as PNV and 64 patients as AMD. We examined the clinical data, analyzed VWF multimer and two genetic polymorphisms (I62V and Y402H) in the CFH. PNV group was significantly younger than AMD group (P = 0.001). In both I62V and Y402H, there were no significant differences between PNV and AMD while the recessive homozygous (AA) was found only in PNV group in I62V. The presence of unusually large VWF multimers (UL-VWFMs) and subretinal hemorrhages were significantly higher in PNV than in AMD (P = 0.045, P = 0.020, respectively). Thus, the residual UL-VWFMs may result in platelet thrombosis and hemorrhages in the choriocapillaris of PNV. In conclusion, our results suggest the biological differences between PNV and AMD.

A novel BMP-2-loaded hydroxyapatite/beta-tricalcium phosphate microsphere/hydrogel composite for bone regeneration.

Although bone morphogenetic protein (BMP) has potent osteoinductivity, the potential adverse events attributed to its burst release prevent its widespread clinical application. Therefore, there is a strong need for BMP delivery systems that maximize osteoinductivity while preventing adverse effects. We evaluated the bone-regenerating potential of NOVOSIS putty (NP), a novel composite combining hydroxyapatite, beta-tricalcium phosphate microsphere/poloxamer 407-based hydrogel, and recombinant human (rh) BMP-2. In vitro assessment of release kinetics by enzyme-linked immunosorbent assay demonstrated sustained release of rhBMP-2 from NP and burst release from collagen sponge (CS), and in vivo assessment of release kinetics by longitudinal tracking of fluorescently labeled rhBMP-2 showed a longer biological half-life of rhBMP-2 with NP than with CS. Furthermore, osteogenic gene expression in MC3T3-E1 cells was significantly higher after co-culture with NP than after co-culture with CS, suggesting that the sustained release of rhBMP-2 from NP effectively contributed to the differentiation of osteoblasts. In a rat spinal fusion model, the volume and quality of newly formed bone was higher in the NP group than in the CS group. Use of NP results in efficient bone regeneration through sustained release of rhBMP-2 and improves the quality of BMP-induced bone.

Clinical implications of pachyvessels in polypoidal choroidal vasculopathy.

BACKGROUND: Polypoidal choroidal vasculopathy (PCV) is one of the disorders within the pachychoroid spectrum diseases. The presence of pachyvessels is one of the characteristics of pachychoroid disorders. However, the relationship between the presence of pachyvessels and the clinical characteristics of PCV eyes has not been determined. The purpose of this study was to determine the relationship between the presence of choroidal pachyvessels and the clinical characteristics of eyes with PCV. METHODS: The medical records of patients who were diagnosed with PCV and were treatment-naïve were reviewed. Fluorescein and indocyanine green angiography, fundus photography, spectral domain optical coherence tomography (SD-OCT), and enhanced depth imaging OCT (EDI-OCT) were used to obtain images of the choroid. The presence of pathologically dilated outer choroidal vessels, pachyvessels, was determined by ICGA images. These pachyvessels were confirmed to correspond with the large choroidal vessels in the EDI OCT images. The PCV eyes were divided into two groups based on the presence or absence of pachyvessels and clinical features and subfoveal choroidal thickness (SFCT) were evaluated between the two groups. RESULTS: Eighty-six eyes of 84 patients with PCV were evaluated. Pachyvessels were detected in 48 eyes (55.8%). The mean SFCT was 203.9 ± 83.9 µm in all 86 eyes, and it was significantly thinner in eyes with pachyvessels (+) than without pachyvessels (-) (183.2 ± 58.4 µm vs 230.2 ± 103.1 µm; P = 0.01). The differences in the incidence of subretinal fluid, pigment epithelial detachments, and hemorrhages between the two groups were not significant. However, the PCV eyes in pachyvessels (+) group with hemorrhage had the thinnest choroid (P = 0.047). The choroidal features of the fellow eyes were similar to those of the PCV affected eyes, that is, the fellow eyes in pachyvessels (+) group had pachyvessels and the fellow eyes in pachyvessels (-) group did not have pachyvessels. CONCLUSIONS: Pachyvessels were presented 55.8% in eyes with PCV, and these eyes had the thin SFCT. The presence of pachyvessels and attenuation of the inner choroid were probably due to the pathological changes in the eyes with PCV.

Effects of concentration of amyloid ß (Aß) on viability of cultured retinal pigment epithelial cells.

BACKGROUND: Amyloid beta (Aß) is a constituent of drusen that is a common sign of age-related macular degeneration (AMD). The purpose of this study was to investigate the effect of Aß on human retinal pigment epithelial (RPE) cells in culture. METHODS: Cells from a human RPE cell line (ARPE-19) were exposed to 0 to 25 µM of Aß 1-40 for 48 h, and the number of living cells was determined by WST-8 cleavage. Replicative DNA synthesis was measured by the incorporation of 5'-bromo-2'-deoxyuridine. The cell death pathway was investigated by the WST-8 cleavage assay after the addition of caspase-9 inhibitor, an anti-apoptotic factor. Real-time qRT-PCR was performed using Aß-exposed cellular RNA to determine the level of vascular endothelial growth factor (VEGF)-A and pigment epithelium derived factor (PEDF). To determine the effect of receptor-for-advanced glycation end products (RAGE), the siRNA for RAGE was inserted into ARPE-19 treated with Aß, and the levels of expression of VEGF-A and PEDF were determined. RESULTS: The number of living ARPE-19 cells was increased by exposure to 5 µM Aß but was decreased by exposure to 25 µM of Aß. Replicative DNA synthesis by ARPE-19 cells exposed to 25 µM of Aß was significantly decreased indicating that 25 µM of Aß inhibited cell proliferation. Real-time RT-PCR showed that the level of the mRNA of PEDF was increased by exposure to 5 µM Aß, and the levels of the mRNAs of PEDF and VEGF-A were also increased by exposure to 25 µM Aß. The addition of an inhibitor of caspase-9 blocked the decrease the number of ARPE-19 cells exposed to 25 µM Aß. Exposure to si-RAGE attenuated the increase of VEGF-A and PEDF mRNA expression in ARPE-19 exposed to Aß. CONCLUSIONS: Exposure of ARPE-19 cells to low concentrations of Aß increases the level of PEDF which then inhibits the apoptosis of ARPE-19 cells leading to RPE cell proliferation. Exposure to high concentrations of Aß induces RPE cell death and enhances the expression of the mRNA of VEGF-A in RPE cells. The Aß-RAGE pathway may lead to the expression VEGF-A and PEDF in RPE cells. These results suggest that Aß is strongly related to the pathogenesis of choroidal neovascularization.

Case of progressive hyperopia due to flattening of cornea.

PURPOSE: To report a case that had a progressive decrease in the visual acuity caused by a progressive increase in the hyperopia due to a flattening of the cornea. OBSERVATIONS: A 50-year-old woman complained of decreased vision in both eyes. Her decimal best-corrected visual acuity was 1.2 in the right and 0.5 in the left eyes, and the refractive error (spherical equivalent) was +3.75 diopters (D) for the right eye and +6.5 D for the left eye. Slit-lamp examinations showed clear corneas but Descemet's folds and fine pigmentations and opacities were present beneath the corneal epithelium in both eyes. Analysis of the corneal shape by anterior segment optical coherence tomography showed that the corneas were flattened, and the corneal refractive power was decreased in both eyes. The large values of the higher-order aberration in the cornea and total eye displayed bilateral irregular astigmatism. She obtained good vision by wearing hard contact lenses but her refractive power continued to decrease for at least 1 year. CONCLUSIONS: and Importance: We report a rare case of progressive hyperopia and irregular astigmatism due to a flattening of the cornea. Folds were present in Descemet's membrane but the cornea was not edematous.

Statins decrease vascular epithelial growth factor expression via down-regulation of receptor for advanced glycation end-products.

AIMS: Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, possess pleiotropic effects that have been extended to modulation of various cellular behaviors. This study aimed to examine whether statins modulate vascular endothelial growth factor A (VEGF-A) expression in human retinal pigment epithelium (RPE) cells. MAIN METHODS: Human RPE cells (h1RPE7), damaged by hydroquinone (HQ) + advanced glycation endproducts (AGE) in an in vitro AMD model, were treated with atorvastatin or lovastatin for 24 h. The expression of VEGF-A and receptor for AGE (RAGE) was evaluated by real-time RT-PCR. VEGF-A secretion was measured by ELISA. To investigate the impact of RAGE on VEGF-A expression, small interfering RNA (siRNA) for RAGE (siRAGE) was introduced into h1RPE7 cells and VEGF-A expression was measured by real-time RT-PCR. Deletions of VEGF-A and RAGE promoters were performed and transcriptional activities were measured after the addition of statins to HQ + AGE-damaged RPE cells. KEY FINDINGS: The mRNA levels of VEGF-A and RAGE and the levels of VEGF-A in the culture medium were increased by HQ + AGE. Both atorvastatin and lovastatin attenuated HQ + AGE-induced VEGF-A and RAGE expression. These statins also decreased VEGF-A levels in the culture medium. RNA interference of RAGE attenuated the up-regulation of VEGF-A in the HQ + AGE treated cells. The deletion analysis demonstrated that these statins attenuated RAGE promoter activation in HQ + AGE-damaged RPE cells. SIGNIFICANCE: Statins attenuated HQ + AGE-induced VEGF expression by decreasing RAGE expression. As VEGF is an important factor in developing wet AMD, statins could decrease the risk of wet-type AMD and be used as preventive medicines.