Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension.

Autophagy has a fundamental role in maintaining cell homeostasis. Although autophagy has been implicated in glaucomatous pathology, how it regulates retinal ganglion cell (RGC) injury is largely unknown. In the present work, we found that biphasic autophagy in RGCs occurred in a mouse model of chronic ocular hypertension (COH), accompanied by activation of Rac1, a member of the Rho family. Rac1 conditional knockout (Rac1 cKO) in RGCs attenuated RGC apoptosis, in addition to blocking the increase in the number of autophagosomes and the expression of autophagy-related proteins (Beclin1, LC3-II/I, and p62) in COH retinas. Electron micrograph and double immunostaining of LAMP1 and LC3B showed that Rac1 cKO accelerated autolysosome fusion in RGC axons of COH mice. Inhibiting the first autophagic peak with 3-methyladenine or Atg13 siRNA reduced RGC apoptosis, whereas inhibiting the second autophagic peak with 3-MA or blocking autophagic flux by chloroquine increased RGC apoptosis. Furthermore, Rac1 cKO reduced the number of autophagosomes and apoptotic RGCs induced by rapamycin injected intravitreally, which suggests that Rac1 negatively regulates mTOR activity. Moreover, Rac1 deletion decreased Bak expression and did not interfere with the interaction of Beclin1 and Bcl-2 or Bak in COH retinas. In conclusion, autophagy promotes RGC apoptosis in the early stages of glaucoma and results in autophagic cell death in later stages. Rac1 deletion alleviates RGC damage by regulating the cross talk between autophagy and apoptosis through mTOR/Beclin1-Bak. Interfering with the Rac1/mTOR signaling pathway may provide a new strategy for treating glaucoma.

Activated ephrinA3/EphA4 forward signaling induces retinal ganglion cell apoptosis in experimental glaucoma.

Previous studies have demonstrated that EphA4 participates in neuronal injury, and there is a strong interaction between ephrinA3 and EphA4. In this study, we showed that in a rat chronic ocular hypertension (COH) experimental glaucoma model, expression of EphA4 and ephrinA3 proteins was increased in retinal cells, including retinal ganglion cells (RGCs) and Müller cells, which may result in ephrinA3/EphA4 forward signaling activation on RGCs, as evidenced by increased p-EphA4/EphA4 ratio. Intravitreal injection of ephrinA3-Fc, an activator of EphA4, mimicked the effect of COH on p-EphA4/EphA4 and induced an increase in TUNEL-positive signals in normal retinas, which was accompanied by dendritic spine retraction and thinner dendrites in RGCs. Furthermore, Intravitreal injection of ephrinA3-Fc increased the levels of phosphorylated src and GluA2 (p-src and p-GluA2). Co-immunoprecipitation assay demonstrated interactions between EphA4, p-src and GluA2. Intravitreal injection of ephrinA3-Fc reduced the expression of GluA2 proteins on the surface of normal retinal cells, which was prevented by intravitreal injection of PP2, an inhibitor of src-family tyrosine kinases. Pre-injection of PP2 or the Ca2+-permeable GluA2-lacking AMPA receptor inhibitor Naspm significantly and partially reduced the number of TUNEL-positive RGCs in the ephrinA3-Fc-injected and COH retinas. Our results suggest that activated ephrinA3/EphA4 forward signaling promoted GluA2 endocytosis, then resulted in dendritic spine retraction of RGCs, thus contributing to RGC apoptosis in COH rats. Attenuation of the strength of ephrinA/EphA signaling in an appropriate manner may be an effective way for preventing the loss of RGCs in glaucoma.

Ocular Biometric Characteristics of Chinese with History of Acute Angle Closure.

PURPOSE: To investigate the biometric characteristics of Chinese patients with a history of acute angle closure (AAC). METHODS: In this clinic-based, retrospective, observational, cross-sectional study, biometric parameters of eyes were acquired from a general population of Chinese adults. The crowding value (defined as lens thickness (LT); central corneal thickness (CCT); anterior chamber depth (ACD)/axial length (AL)) was calculated for each patient. Logistic regression analysis was performed to identify risk factors for AAC. Receiver operating characteristic (ROC) curves were plotted, and biometric variables were compared to compile a risk assessment for AAC. RESULT: This study included 1500 healthy subjects (2624 eyes, mean age of 66.54 ± 15.82 years) and 107 subjects with AAC (202 eyes, mean age of 70.01 ± 11.05 years). Eyes with AAC had thicker lens (P ≤ 0.001), shallower anterior chamber depth (P ≤ 0.001), and shorter axial length (P ≤ 0.001) than healthy eyes. Logistic regression analysis and ROC curve analysis indicated that a crowding value above 0.13 was a significant (P < 0.05) risk factor for the development of AAC. CONCLUSIONS: Biometric parameters were significantly different between the eyes from the AAC group to the normal group. Ocular crowding value might be a new noncontact screening method to assess the risk of AAC in adults.

Analysis of corneal astigmatism in cataract surgery candidates at a teaching hospital in Shanghai, China.

PURPOSE: To describe and quantify the pattern of corneal astigmatism in cataract surgery candidates and to provide information for cataract surgeons and intraocular lens (IOL) manufacturers. SETTING: Zhongshan Hospital, Fudan University, Shanghai, China. DESIGN: Cross-sectional study. METHODS: The datasets of cataract surgery candidates acquired between November 1, 2009, and November 30, 2011, were collected and analyzed. Keratometry values were optically measured by partial coherence interferometry (IOLMaster) before cataract extraction. Spearman rank correlation coefficients were used to estimate bivariate correlations. The power vector method, J(0) and J(45) values, and linear regression models were used to assess the association between age and astigmatism. RESULTS: The study evaluated the keratometry values in 1430 eyes (827 patients) with a median age of 75 years (range 16 to 98 years). The corneal astigmatism was 1.00 diopter (D) or higher in 45.45% of eyes. The magnitude of corneal astigmatism was positively correlated with age (ρ = 0.126, P = .000). A trend toward increasing against-the-rule astigmatism with age was found by linear regression models; the per-year increase in age was associated with a J(0) decrease of 0.016 D in right eyes and 0.018 D in left eyes (both P = .000). No association was found between age and J(45). CONCLUSIONS: Most eyes having corneal astigmatism of 1.00 D or greater could be covered by the range of the cylindrical power of the toric IOLs available on the market. Against-the-rule corneal astigmatism of relatively younger cataract surgery candidates should be managed more aggressively. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Time course of Q value after myopic laser-assisted in situ keratomileusis.

OBJECTIVE: To assess the time course of Q value after myopic laser-assisted in situ keratomileusis (LASIK) and preliminarily evaluate the determinants of the difference of Q value between before and after LASIK. METHODS: We performed a retrospective, longitudinal investigation on patients undergoing wavefront optimized LASIK therapy for emmetropization. A total of 418 eyes from 222 cases were examined preoperatively, and partly followed up at one week (172 eyes), one month (134 eyes) and three months (51 eyes) after surgery. The horizontal, vertical and total Q values of cornea were calculated from eccentricity measured at the central 6-mm corneal zones respectively. Potential determinants of the change of Q value were analyzed using multiple linear regressions. RESULTS: The mean Q value was -0.17 +/- 0.13 preoperatively, and 0.99 +/- 0.70, 0.97 +/- 0.66, and 0.86 +/- 0.41 one week, one and three months postoperatively, respectively. One way analysis of variance (ANOVA) demonstrated significant differences between measurements made before surgery and at all postoperative times (at one week, one and three months; all P<0.0001, Bonferroni post hoc), but no significant differences were found among postoperative groups. Significant differences of Q values between horizontal and vertical meridians were found before surgery and at all postoperative times (all P<0.0001). Multiple regression analysis revealed that change of Q value significantly correlated with manifest refraction spherical equivalent (r=0.116, P<0.0001) and axial length (r=0.264, P<0.0001). CONCLUSIONS: Over the study period, the primary changes in Q value occur within 1 week after surgery, and then become slightly decreased and nearly stable. Manifest refraction spherical equivalent and axial length play a significant role in the change of postoperative Q value.