Pathogenesis Of Primary Open-angle Glaucoma Research Articles

Analysis of retinal arteriolar and venular parameters in primary open angle glaucoma.

To measure the retinal vessels of primary open angle glaucoma (POAG) patients on spectral domain optical coherence tomography (SD-OCT) with a full-width at half-maximum (FWHM) algorithm to better explore their structural changes in the pathogenesis of POAG. In this retrospective case-control study, the right eyes of 32 patients with POAG and 30 healthy individuals were routinely selected. Images of the supratemporal and infratemporal retinal vessels in the B zones were obtained by SD-OCT, and the edges of the vessels were identified by the FWHM method. The internal and external diameters, wall thickness (WT), wall cross-sectional area (WCSA) and wall-to-lumen ratio (WLR) of the blood vessels were studied. Compared with the healthy control group, the POAG group showed a significantly reduced retinal arteriolar outer diameter (RAOD), retinal arteriolar lumen diameter (RALD) and WSCA in the supratemporal (124.22±12.42 vs 138.32±10.73 µm, 96.09±11.09 vs 108.53±9.89 µm, and 4762.02±913.51 vs 5785.75±1148.28 µm2, respectively, all P<0.05) and infratemporal regions (125.01±15.55 vs 141.57±10.77 µm, 96.27±13.29 vs 110.83±10.99 µm, and 4925.56±1302.88 vs 6087.78±1061.55 µm2, all P<0.05). The arteriolar WT and WLR were not significantly different between the POAG and control groups, nor were the retinal venular outer diameter (RVOD), retinal venular lumen diameter (RVLD) or venular WT in the supratemporal or infratemporal region. There was a positive correlation between the arteriolar parameters and visual function. In POAG, narrowing of the supratemporal and infratemporal arterioles and a significant reduction in the WSCA is observed, while the arteriolar WT and WLR do not change. Among the venular parameters, the external diameter, internal diameter, WT, WLR, and WSCA of the venules are not affected.

Molecular genetics of primary open-angle glaucoma.

Glaucoma is a series of linked optic diseases resulting in progressive vision loss and total blindness due to the acquired loss of retinal ganglion cells. This harm to the optic nerve results in visual impairment and, ultimately, total blindness if left untreated. Primary open-angle glaucoma (POAG) is the most frequent variety within the large family of glaucoma. It is a multifaceted and heterogeneous condition with several environmental and genetic variables aiding in its etiology. By 2040, there will be 111.8 million glaucoma patients globally, with Asia and Africa accounting for the vast majority. The goal of this review is to elaborate on the role of genes (nuclear and mitochondrial) as well as their variants in the pathogenesis of POAG. PubMed and Google Scholar databases were searched online for papers until September 2022. Prevalence and inheritance patterns vary significantly across different ethnic and geographic populations. Numerous causative genetic loci may exist; however, only a few have been recognized and characterized. Further investigation into the genetic etiology of POAG is expected to uncover novel and intriguing causal genes, allowing for a more precise pathogenesis pattern of the disease.

Aqueous humor cytokine levels are associated with the severity of visual field defects in patients with primary open-angle glaucoma

BackgroundTo evaluate the aqueous humor (AH) levels of cytokines in primary open-angle glaucoma (POAG) patients and cataract patients.MethodsThirty-eight POAG patients and 26 cataract patients were recruited. Peripheral blood (PB) was collected from each subject. The POAG group was divided into 2 subgroups according to the severity of visual field defects. The cutoff point of the mean deviation (MD) of the visual field was -12 dB. AH was obtained at the time of anterior chamber puncture during cataract or glaucoma surgery by using a 27-gauge needle attached to a microsyringe. AH and PB levels of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta2 (TGF-β2) and IL-4 were assayed by enzyme-linked immunosorbent assay. Postoperative intraocular pressures (IOPs) of POAG patients were recorded during the follow-up period.ResultsTNF-α and TGF-β2 showed significantly higher AH levels in the POAG group than in the cataract group (P < 0.001 and P = 0.001, respectively). For the POAG group, preoperative IOPs were significantly positively correlated with AH levels of TNF-α (r2 = 0.129, P = 0.027) and TGF-β2 (r2 = 0.273, P = 0.001). AH levels of TGF-β2 were significantly different among cataract patients, POAG patients with MD> -12 dB and POAG patients with MD≤ -12 dB (P = 0.001). AH levels of TNF-α were significantly positively associated with IOP reduction after trabeculectomy (P = 0.025). AH and PB levels of cytokines were not related to the long-term success of trabeculectomy.ConclusionThe levels of TNF-α and TGF-β2 showed different profiles in POAG patients and cataract patients. AH levels of TGF-β2 were correlated with the severity of glaucomatous neuropathy in POAG patients. The findings suggest possible roles for cytokines in the pathogenesis and development of POAG.

Integrated aqueous humor ceRNA and miRNA-TF-mRNA network analysis reveals potential molecular mechanisms governing primary open-angle glaucoma pathogenesis.

To conduct an integrated bioinformatics analysis of extant aqueous humor (AH) gene expression datasets in order to identify key genes and the regulatory mechanism governing primary open-angle glaucoma (POAG) progression. Two datasets (GSE101727 and GSE105269) were downloaded from the Gene Expression Omnibus, and the messenger RNAs (mRNAs), microRNAs (miRNAs), and long noncoding RNAs (lncRNAs) were identified between controls and POAG patients. Differentially expressed (DE) mRNAs and DElncRNAs were then subjected to pathway enrichment analyses, after which a protein-protein interaction (PPI) network was generated. This network was then expanded to establish lncRNA-miRNA-mRNA and miRNA-transcription factor (TF)-mRNA networks. The GSE101727 dataset was used to identify 2746 DElncRNAs and 2208 DEmRNAs, while the GSE105269 dataset was used to identify 45 DEmiRNAs. We ultimately constructed a competing endogenous RNA (ceRNA) network incorporating 47 lncRNAs, six miRNAs, and 17 mRNAs. The proteins encoded by these 17 hub mRNAs were found to be significantly enriched for activities that may be linked to POAG pathogenesis. In addition, we generated a miRNA-TF-mRNA regulatory network containing two miRNAs (miR-135a-5p and miR-139-5p), five TFs (TGIF2, TCF3, FOS, and so on), and five mRNAs (SHISA7, ST6GAL2, TXNIP, and so on). The SHISA7, ST6GAL2, TXNIP, FOS, and DCBLD2 genes may be viable therapeutic targets for the prevention or treatment of POAG and are regulated by the TFs (TGIF2, HNF1A, TCF3, and FOS).

Association between Serum Total Bilirubin Level and Patients with Primary Open-Angle Glaucoma in China: A Cross-Sectional, Case-Control Study.

To investigate the relationship between peripheral blood total bilirubin (TBIL) levels and the risk of primary open-angle glaucoma (POAG). This study was a cross-sectional, case-control study design. Between April 2021 and January 2022, 198 POAG patients and 205 healthy subjects were recruited from the EENT Hospital of Fudan University. Their clinical information (intraocular pressure, central corneal thickness, vertical cup-disk ratios (VCDR), and axial length) and demographic data were collected. Serum levels of TBIL were measured in enzymes using a Roche C702 biochemical analyzer. The POAG subgroups were classified by gender and VCDR: mild (VCDR ≤ 0.64), moderate (VCDR ≤ 0.85), and severe (VCDR > 0.85). Univariate and multivariate logistic regression analyses were performed. The level of TBIL (11.58 ± 5.16 μmol/L) in the POAG group was higher than that in the control group (10.18 ± 3.38 μmol/L; p < 0.05). In the male subgroup, TBIL was also significantly higher than in the normal control group; TBIL levels were lower in the mild subgroup (10.82 ± 4.48 μmol/L), followed by the moderate subgroup (12.00 ± 5.55 μmol/L) and the severe subgroup (14.47 ± 5.45 μmol/L). The results of the multivariate logistic regression analysis showed that high TBIL levels were a risk factor for male POAG, at 1.126 (95% CI 1.009-1.256). Pearson's analysis revealed that TBIL was positively correlated with intraocular pressure (r = 0.134, p = 0.012), VCDR (r = 0.142, p = 0.046), anterior chamber depth (r = 0.190, p = 0.014), and axial length (r = 0.179, p = 0.019) in the patients. However, no statistical difference (p < 0.05) was observed in the female patients with POAG. The results showed that high levels of TBIL may be related to the pathogenesis of POAG and that the severity of the disease is positively correlated, especially in male patients.

Association between Serum Uric Acid Levels and Primary Open-angle Glaucoma: A Cross-sectional Study

Introduction: There is an intricate association between serum Uric Acid (UA) levels and Primary Open Angle Glaucoma (POAG). UA levels in the blood are known to be a good indicator of antioxidant function, and a decrease in UA plays a key role in the pathogenesis of POAG. However, the association of serum UA and Uric Acid Creatinine Ratio (UACR) in POAG cases in the Indian population remains unexplored. Aim: To investigate the association of serum UA levels and serum UACR with POAG. Materials and Methods: This cross-sectional study was conducted among patients who attended the Outpatient Department (OPD) of Opthalmology at Maharajah’s Institute of Medical Sciences, Vizianagaram, Andhra Pradesh, India. The duration of the study was one year and six months, from January 15, 2021 to July 15, 2022. The study included 200 recently diagnosed patients with POAG, who were divided into three groups based on Intraocular Pressure (IOP): Group 1 (mild) with an IOP of 21-30 mmHg, group 2 (moderate) with an IOP of 31-50 mmHg, and group 3 (severe) with an IOP greater than 51 mmHg. Age and gender-matched 199 healthy subjects were included as the control group. Blood samples were collected from the study subjects after obtaining informed consent and were tested for serum UA (using the modified Trinder method) and serum creatinine (using Jaffe’s method) in a semiautomatic analyser (Erba chem 7). The data were analysed using Statistical Package for Social Sciences (SPSS) version 21.0 software and MS Excel 2007. Results: The mean age of the study participants of all three groups was found to be 51.19±5.06 years with 46.7% male and 53.3% female subjects. The serum UA levels were 5.55±0.74 mg/dL in the mild POAG group, 4.1±0.5 mg/dL in the moderate POAG group, and 2.67±0.6 mg/dL in the severe POAG group (p-value &lt;0.001). The present study also found that among the three study groups of POAG, UA levels were the lowest in the severe POAG group, followed by the moderate POAG group, and then the mild POAG group. This pattern was observed in both the males and females population. Conclusion: The present study found that serum UA levels were decreased in POAG patients compared to the normal healthy control group. Furthermore, the study revealed a significant negative association between serum UA levels and serum UACR levels with the severity of POAG.

Cell senescence alters responses of porcine trabecular meshwork cells to shear stress.

Mechanical microenvironment and cellular senescence of trabecular meshwork cells (TMCs) are suspected to play a vital role in primary open-angle glaucoma pathogenesis. However, central questions remain about the effect of shear stress on TMCs and how aging affects this process. We have investigated the effect of shear stress on the biomechanical properties and extracellular matrix regulation of normal and senescent TMCs. We found a more significant promotion of Fctin formation, a more obvious realignment of F-actin fibers, and a more remarkable increase in the stiffness of normal cells in response to the shear stress, in comparison with that of senescent cells. Further, as compared to normal cells, senescent cells show a reduced extracellular matrix turnover after shear stress stimulation, which might be attributed to the different phosphorylation levels of the extracellular signal-regulated kinase. Our results suggest that TMCs are able to sense and respond to the shear stress and cellular senescence undermines the mechanobiological response, which may lead to progressive failure of cellular TM function with age.

Progression of functional and structural glaucomatous damage in relation to diurnal and nocturnal dips in mean arterial pressure.

Systemic hypoperfusion plays a pivotal role in the pathogenesis of primary open-angle glaucoma (POAG). Extreme dips in mean arterial pressure (MAP) due to high 24-h variability are associated with POAG, however, whether this is driven by diurnal or nocturnal dips remains undocumented. We aimed this study to investigate the association of POAG damage with variability and dips in the diurnal and nocturnal MAP. We conducted a retrospective longitudinal study that included 110 POAG patients who underwent 24-h ambulatory blood pressure monitoring. Our outcomes included (i) functional [visual field defects expressed as mean deviation (MD)] and (ii) structural (optic disc cupping obtained from cup-to-disc ratio) glaucoma damage. MAP variability independent of the mean (VIMmap) was computed for diurnal and nocturnal MAP. Dips were the five diurnal and three nocturnal lowest drops in MAP. We also calculated the night-to-day ratio. We applied mixed models to evaluate the progression of visual field defects and optic disc cupping in relation to diurnal and nocturnal MAP measures. The mean age was 64.0 y (53% women). The median follow-up was 9 years. In adjusted mixed models, functional progression of glaucoma damage was associated with VIMmap (-2.57 dB change in MD per every 3 mmHg increase in VIMmap; P < 0.001) and diurnal MAP dips (changes in the MD ranged from -2.56 to -3.19 dB; P < 0.001). Every 5 mmHg decrease in the nocturnal MAP level was associated with -1.14 dB changes in MD [95% confidence interval (CI), -1.90 to -0.40] and 0.01 larger optic disc cupping (95% CI, 0.01-0.02). Lower night-to-day ratio was also related to both outcomes (P ≤ 0.012). Functional glaucoma damage worsened if nocturnal hypotension was combined with high variability or extreme dips in the diurnal MAP (P ≤ 0.022). Progression of glaucoma damage in POAG associates with high variability and extreme dips in the diurnal MAP. Structural glaucoma damage seems more vulnerable to nocturnal hypotension. Ambulatory blood pressure monitoring allows the assessment of sporadic diurnal and persistent nocturnal hypotension episodes. These phenotypes might offer an opportunity to improve the risk-stratification of open-angle glaucoma (OAG).

Association between polymorphic &lt;i&gt;eNOS&lt;/i&gt; gene markers and risk of primary open-angle glaucoma in the Perm Region population

Glaucoma is widely known to have a progressive course and occupy a leading place among the causes of vision loss and blindness. Increased intraocular pressure is the key harmful factor among the causes of glaucoma occurrence. In some cases, however, the progressive disease is also observed at normal values of ophthalmic tonus. Early diagnosis of glaucoma will allow for timely therapy, which in turn will reduce the risk of complications and prevent neuroopticopathy progression. According to the literature data, the pathogenesis of primary open-angle glaucoma is associated with nitric oxide (NO), due to imbalance between endothelium-produced vasoconstrictors and vasodilators, especially, endotelin-1 and nitric oxide. Decreased NO level combined with endotelin-1 hyperproduction is associated with development and progression of a number of ocular disorders including glaucomatous atrophy of the optic nerve. Since nitric oxide is produced by endothelial NO-synthase (eNOS), one may assume that eNOS is involved in pathogenesis of neurodegenerative changes in primary open-angle glaucoma. However, despite numerous studies on the pathogenesis of glaucoma, the distinct factors of innate immune response remain poorly studied. The purpose of the present study was a search for association between polymorphic markers (C774T, T786C, Glu298Asp) of the eNOS gene and the risk of primary open-angle glaucoma among the Perm Region residents.&#x0D; Peripheral blood of patients with primary open-angle glaucoma (the main group) and cataract without glaucoma (a comparison group) was used as initial biomaterial. In comparison group, arterial hypertension was most often encountered as concomitant pathology. Genomic DNA was first isolated from the blood samples, followed by rt-PCR using reagent kits for determining C774T, T786C, Glu298Asp polymorphic markers in the eNOS gene.&#x0D; The prevalence of polymorphic variants of the innate immunity genes T786C, C774T and Glu298Asp of the eNOS gene was analyzed in patients with primary open-angle glaucoma. There were no significant differences in the distribution of genotypes and alleles of eNOS gene for the C774T and Glu298Asp polymorphic markers. An increased frequency of homozygous TT genotype was found, along with decreased occurrence of C allele at the polymorphic T786C locus of the eNOS gene, as well as a trend for decreased frequency of the TC and CC genotypes. Arterial hypertension potentiated the negative effect of increased intraocular pressure upon the glaucoma-associated optic neuropathy. Conclusions. The studied changes in genotypes and allelic frequencies of eNOS gene may be regarded as risk factors that increase probability of the primary open-angle glaucoma and predict severity of the disease.

The role of Vitamin D3 in ocular fibrosis and its therapeutic potential for the glaucomatous trabecular meshwork.

Glaucoma is the leading cause of irreversible blindness globally. The most prevalent subtype, Primary Open Angle Glaucoma (POAG), is characterized by increased intraocular pressure (IOP), damage to the optic nerve head and irreversible visual loss. IOP increases aqueous humor (AqH) outflow is reduced through the trabecular meshwork (TM) and Schlemm's canal (SC). Increased outflow resistance is partly due to TM/SC dysregulation, including loss of normal trabecular meshwork cell (TMC) function, following increased levels of oxidative stress within TMC, dysregulated extracellular matrix (ECM) deposition and remodeling alongside alterations in TMC phenotype and apoptosis. Current widely available POAG treatments do not target the aberrant expression of ECM in the TM directly. As a result, most drug treatments can fail as the underlying pathological process continues unabated. Rho-kinase inhibitors have demonstrated the benefit of restoring TM/SC function, however there is a clear need to develop further treatment strategies that can target the underlying cellular processes which become dysregulated within the TMC during POAG pathogenesis. Vitamin D is suggested to be beneficial in alleviating the symptoms of fibrosis and inflammation in soft tissues. It has important functions in many major organ systems, including regulation of calcium, phosphate and parathyroid hormone. Evidence suggests that Vitamin D3 modulates ECM turnover through the conventional TGFβ-SMAD signaling, which is associated with the development of POAG. The link between Vitamin D3, inflammation and fibrosis within ocular tissues will be discussed and the potential roles of Vitamin D3 in the management of POAG patients will be explored within this review.

The Role of Oxidative Status in the Pathogenesis of Primary Open-Angle Glaucoma, Pseudoexfolyation Syndrome and Glaucoma.

To investigate the role of oxidative stress and antioxidant system in the etiopathogenesis of pseudoexfoliation and progression of pseudoexfoliation syndrome to glaucoma. A total of 20 patients with pseudoexfoliation syndrome, 20 with pseudoexfoliation glaucoma, 20 with primary open-angle glaucoma, and 20 without pseudoexfoliation and glaucoma as a control group, who underwent cataract or glaucoma surgery between December 2020 and March 2021 in the Health Sciences University Beyoğlu Eye Training and Research Hospital, 80 patients were included in the study. Best corrected visual acuity (BCVA), intraocular pressure with applanation tonometry, detailed anterior and posterior segment examinations with biomicroscopy were performed in all patients included in the study. Approximately 0.1 cc of anterior chamber fluid was taken from all patients at the beginning of surgery. Total Oxidant Status (TOS) and Total Antioxidant Status (TAS) levels were measured by keeping the samples taken in the deep freezer of the cornea bank at -80 degrees, transferring them with cold chain transport rules, and examining them with automatic measurement method in the laboratories of the Medical Biochemistry Department of the University of Health Sciences. Oxidative Stress Index (OSI) value was calculated to measure the degree of oxidative stress. TAS averages of the control and POAG groups were found to be statistically significantly higher than the PES and PEG groups (p = 0.0001, p = 0.0001). No significant difference was observed between the other groups (p > 0.05). The TOS averages of the control and POAG groups were found to be statistically significantly lower than the PES and PEG groups (p = 0.003, p = 0.0001; p = 0.01, p = 0.001), no statistically significant difference was observed between the other groups (p > 0.05). The OSI mean of the control and POAG groups was found to be statistically significantly lower than the PES and PEG groups (p = 0.001, p = 0.0001; p = 0.002, p = 0.0001), no statistically significant difference was observed between the other groups (p > 0.05). Increased TOS and OSI and decreased TAS levels in the aqueous humour of patients with PES and PEG suggest that increased oxidative stress and decreased antioxidative defense system play a role in the etiopathogenesis of the disease.

PRIMARY OPEN-ANGLE GLAUCOMA DUE TO MUTATIONS IN THE MYOC GENE.

Mutations in the myocilin gene (MYOC) cause trabecular dysfunction and thus are involved in the pathogenesis of primary open-angle glaucoma (POAG). The aim of this study was to characterize and describe the clinical findings in two Czech families with POAG due to pathogenic variants in the MYOC gene. Members of the two families affected by POAG underwent complete ophthalmological examination. In the proband from the first family, a direct sequencing of the three most frequent mutations in the MYOC gene was performed, and in the proband from the second family, an exome sequencing was performed. Other family members underwent targeted tests using direct sequencing. In total, 10 individuals diagnosed with POAG aged 20-70 years (mean 32.2 years, SD ±10,9 years) were examined. Eight of them showed advanced glaucomatous neuropathy with severe changes in the retinal nerve fiber layer. Clinical signs of POAG were present in six individuals in the third decade of life already; another four developed POAG during the fourth decade of life. Eight out of 10 patients had to undergo filtration surgery. Surgery was performed within 1 to 7 years of diagnosis, but mostly was performed within 2 years of glaucoma diagnosis. In the first family, MYOC variant c.1099G&gt;A p.(Gly367Arg) was shown in the affected family members; in the second family MYOC variant c.1440C&gt;A p.(Asn480Lys), both in heterozygous state. The changes were assessed as pathogenic. Our study is the first to describe mutations in the MYOC gene causing POAG in Czech patients. Genetic testing may be recommended for this diagnosis, especially in individuals with early presentation and a positive family history. Carriers of pathogenic variants of the MYOC gene have a lifetime risk of developing POAG of more than 50% and the course of their disease is often more aggressive, requiring surgical intervention to permanently control the intraocular pressure.

Genome-wide transcriptome profiling of human trabecular meshwork cells treated with TGF-β2

Glaucoma is a complex neurodegenerative disease resulting in progressive optic neuropathy and is a leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the predominant form affecting 65.5 million people globally. Despite the prevalence of POAG and the identification of over 120 glaucoma related genetic loci, the underlaying molecular mechanisms are still poorly understood. The transforming growth factor beta (TGF-β) signalling pathway is implicated in the molecular pathology of POAG. To gain a better understanding of the role TGF-β2 plays in the glaucomatous changes to the molecular pathology in the trabecular meshwork, we employed RNA-Seq to delineate the TGF-β2 induced changes in the transcriptome of normal primary human trabecular meshwork cells (HTM). We identified a significant number of differentially expressed genes and associated pathways that contribute to the pathogenesis of POAG. The differentially expressed genes were predominantly enriched in ECM regulation, TGF-β signalling, proliferation/apoptosis, inflammation/wound healing, MAPK signalling, oxidative stress and RHO signalling. Canonical pathway analysis confirmed the enrichment of RhoA signalling, inflammatory-related processes, ECM and cytoskeletal organisation in HTM cells in response to TGF-β2. We also identified novel genes and pathways that were affected after TGF-β2 treatment in the HTM, suggesting additional pathways are activated, including Nrf2, PI3K-Akt, MAPK and HIPPO signalling pathways. The identification and characterisation of TGF-β2 dependent differentially expressed genes and pathways in HTM cells is essential to understand the patho-physiology of glaucoma and to develop new therapeutic agents.

Magnesium and Its Role in Primary Open Angle Glaucoma; A Novel Therapeutic?

Glaucoma is the leading cause of irreversible blindness globally, with Primary open angle glaucoma (POAG) being the commonest subtype. POAG is characterized by an increase in intraocular pressure (IOP), leading to optic nerve damage and subsequent visual field defects. Despite the clinical burden this disease poses, current therapies aim to reduce IOP rather than targeting the underling pathogenesis. Although the pathogenesis of POAG is complex, the culprit for this increase in IOP resides in the aqueous humour (AH) outflow pathway; the trabecular meshwork (TM) and Schlemm's canal. Dysfunction in these tissues is due to inherent mitochondrial dysfunction, calcium influx sensitivity, increase in reactive oxygen species (ROS) production, TGFβ-2 induction, leading to a sustained inflammatory response. Magnesium is the second most common intracellular cation, and is a major co-factor in over 300 reactions, being highly conserved within energy-dependent organelles such as the mitochondria. Magnesium deficiency has been observed in POAG and is linked to inflammatory and fibrotic responses, as well as increased oxidative stress (OS). Magnesium supplementation been shown to reduce cellular ROS, alleviate mitochondrial dysregulation and has further antifibrotic and anti-inflammatory properties within ocular tissues, and other soft tissues prone to fibrosis, suggesting that magnesium can improve visual fields in patients with POAG. The link between magnesium deficiency and glaucoma pathogenesis as well as the potential role of magnesium supplementation in the management of patients with POAG will be explored within this review.

Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells.

Trabecular meshwork dysfunction is the main cause of primary open angle glaucoma (POAG) associated with elevated intraocular pressure (IOP). Mutant myocilin causes glaucoma mainly via elevating IOP. Previously we have found that accumulated Asn 450 Tyr (N450Y) mutant myocilin impairs human trabecular meshwork (TM) cells by inducing chronic endoplasmic reticulum (ER) stress response in vitro. However, it is unclear how ER stress leads to TM damage and whether N450Y myocilin mutation is associated with POAG in vivo. Here we found that N450Y mutant myocilin induces autophagy, which worsens cell viability, whereas inhibition of autophagy increases viability and decreases cell death in human TM cells. Furthermore, we construct a transgenic mouse model of N450Y myocilin mutation (Tg-MYOCN450Y) and Tg-MYOCN450Y mice exhibiting glaucoma phenotypes: IOP elevation, retinal ganglion cell loss and visual impairment. Consistent with our published in vitro studies, mutant myocilin fails to secrete into aqueous humor, causes ER stress and actives autophagy in Tg-MYOCN450Y mice, and aqueous humor dynamics are altered in Tg-MYOCN450Y mice. In summary, our studies demonstrate that activation of autophagy is correlated with pathogenesis of POAG.

Asian Race and Primary Open-Angle Glaucoma: Where Do We Stand?

Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by irreversible retinal ganglion cell damage and visual field loss. The global POAG prevalence is estimated to be 3.05%, and near term is expected to significantly rise, especially within aging Asian populations. Primary angle-closure glaucoma disproportionately affects Asians, with up to four times greater prevalence of normal-tension glaucoma reported compared with high-tension glaucoma. Estimates for overall POAG prevalence in Asian populations vary, with Chinese and Indian populations representing the majority of future cases. Structural characteristics associated with glaucoma progression including the optic nerve head, retina, and cornea are distinct in Asians, serving as intermediates between African and European descent populations. Patterns in IOP suggest some similarities between races, with a significant inverse relationship between age and IOP only in Asian populations. Genetic differences have been suggested to play a role in these differences, however, a clear genetic pattern is yet to be established. POAG pathogenesis differs between Asians and other ethnicities, and it may differ within the broad classification of the Asian race. Greater awareness and further research are needed to improve treatment plans and outcomes for the increasingly high prevalence of normal tension glaucoma within aging Asian populations.

CCN2/CTGF-A Modulator of the Optic Nerve Head Astrocyte.

In primary open-angle glaucoma (POAG), a neurodegenerative disease of the optic nerve (ON) and leading cause of blindness, the optic nerve head (ONH) undergoes marked structural extracellular matrix (ECM) changes, which contribute to its permanent deformation and to degeneration of ON axons. The remodeling process of the ECM causes changes in the biomechanical properties of the ONH and the peripapillary sclera, which is accompanied by an increased reactivity of the resident astrocytes. The molecular factors involved in the remodeling process belong to the Transforming growth factor (TGF)-β superfamily, especially TGF-β2. In previous publications we showed that TGF-β2 induced ECM alterations are mediated by Cellular Communication Network Factor (CCN)2/Connective Tissue Growth Factor (CTGF) and recently we showed that CCN2/CTGF is expressed by astrocytes of the ON under normal conditions. In this study we wanted to get a better understanding of the function of CCN2/CTGF under normal and pathologic conditions. To this end, we analyzed the glial lamina and peripapillary sclera of CCN2/CTGF overexpressing mice and studied the effect of CCN2/CTGF and increasing substratum stiffness on murine ON astrocytes in vitro. We observed enhanced astrocyte reactivity in the ONH, increased ECM protein synthesis in the peripapillary sclera and increased Ccn2/Ctgf expression in the ONH during the pathologic development in situ. CCN2/CTGF treatment of primary murine ON astrocytes induced a higher migration rate, and increase of ECM proteins including fibronectin, elastin and collagen type III. Furthermore, the astrocytes responded to stiffer substratum with increased glial fibrillary acidic protein, vimentin, actin and CCN2/CTGF synthesis. Finally, we observed the reinforced appearance of CCN2/CTGF in the lamina cribrosa of glaucomatous patients. We conclude that reactive changes in ONH astrocytes, induced by the altered biomechanical characteristics of the region, give rise to a self-amplifying process that includes increased TGF-β2/CCN2/CTGF signaling and leads to the synthesis of ECM molecules and cytoskeleton proteins, a process that in turn augments the stiffness at the ONH. Such a scenario may finally result in a vicious circle in the pathogenesis of POAG. The transgenic CTGF-overexpressing mouse model might be an optimal model to study the chronic pathological POAG changes in the ONH.

Positive Association between Aqueous Humor Hydroxylinoleate Levels and Intraocular Pressure.

We previously proposed the total assessment of hydroxylinoleates (HODEs) by LC-MS/MS after saponification and reduction of the biologic samples as biomarkers to investigate pathogenesis, disease progression, and prognosis. In this study, HODE levels were estimated in aqueous humor (AH) samples from 63 eyes (41 Japanese subjects; 15 men; mean age, 77.3 ± 6.8 years) with primary open-angle glaucoma (POAG) or cataracts. The correlations between intraocular HODE levels and background parameters, including intraocular pressure (IOP), were analyzed to assess the possible involvement of oxidative stress in glaucoma pathology. Univariate analyses showed that linoleic acid (LA) (p = 0.034) and arachidonic acid (AA) (p = 0.0041) levels were associated negatively with age; 13-(Z,E)-HODE (p = 0.018) and 13-(E,E)-HODE (p = 0.021) were associated positively with IOP; 9-(Z,E)-HODE (p = 0.039), 13-(Z,E)-HODE (p = 0.021), totally assessed-HODE (t-HODE, p = 0.023), LA (p = 0.0080), and AA (p = 0.0051) were higher in eyes with glaucoma than cataract. No gender differences were seen. A mixed-effect regression model showed that higher 13-(Z,E)-HODE (p = 0.0040) and higher t-HODE (p = 0.040) were associated with glaucoma rather than cataracts; and higher levels of 13-(Z,E)-HODE/LA (p = 0.043), 13-(E,E)-HODE/LA (p = 0.042), 13-(Z,E)-HODE (p = 0.0054), and 13-(E,E)-HODE (p = 0.027) were associated with higher IOP. Linoleate-derived oxidation products were quantified successfully in AH samples from patients with glaucoma and cataracts. A free radical oxidation mechanism can be associated with IOP elevation, while enzymatic oxidation may be involved, specifically, in the pathogenesis of POAG.

The role of eNOS gene polymorphisms in immunopathogenesis of primary open-angle glaucoma

Introduction. Pathologies of the visual organ (keratitis, glaucoma, etc.) occupy a leading place among the causes of vision loss and blindness. According to the literature, the immunopathogenesis of bacterial keratitis is associated with the activation of macrophages and oxygen explosion. The role of these mechanisms in the pathogenesis of primary open-angle glaucoma is not fully understood. There are isolated studies in which the development of this pathology is associated with nitric oxide NO, which is produced by endothelial NO synthase (nos). However, despite numerous studies, the role of immunogenetics in the pathogenesis of glaucoma remains insufficiently researched.The aim of the study is to explore the association of T786C, C774T, Glu298Asp polymorphic markers of the eNOS gene with development of POAG in residents of the Perm Territory.Materials and methods. The study was performed using peripheral blood collected from 93 patients with POAG and 96 patients with cataracts. The real-time polymerase chain reaction was performed after the DNA extraction. The frequencies of alleles and genotypes in the study groups were measured using the chi-square (χ2 ) test and Fisher’s exact test. Results with p 0.05 were seen as statistically significant. The calculated odds ratio and the 95% confidence interval were used to quantify the association between POAG development in patients and the existence of an unfavorable polymorphic marker.Results. The C774T and Glu298Asp markers did not show any significant differences in the distribution of genotypes and alleles of the eNOS gene. Higher frequencies of the homozygous TT genotype; and lower frequencies of the C allele of T786C polymorphic locus of eNOS gene were detected in patients with POAG.Conclusion. Polymorphic markers of the eNOS gene can be seen as factors associated with the risk of POAG.

Myocilin Mutations in a Zambian Population Attending Selected Referral Eye Health Facilities

Purpose: Research has shown that primary open-angle glaucoma (POAG) in Zambia has an earlier age of onset and is more clinically severe than in Europe and the United States of America. Mutations of Myocilin have been reported to be associated with POAG in multiple populations. We therefore, investigated the role of myocilin gene mutations in Primary Open Angle Glaucoma in a Zambian population. Methods: The unrelated POAG patients and unaffected controls seen at the University Teaching Hospitals Eye Hospital, Kitwe Teaching Eye Hospital and Lusaka Eye Hospital were recruited for this study. Glaucoma specialists from the participating institutions ascertained all POAG and control patients. Age, sex and ethnicity matched unaffected controls were obtained in patients with an IOP &lt; 22 mm Hg, clear ocular media and normal-appearing optic nerve heads. A complete eye examination, including visual field assessment, was performed in all cases. Genomic DNA was extracted from whole peripheral blood, then subjected to polymerase chain reaction to amplify exons, flanking introns and promoter regions of the myocilin gene. The amplified products were screened for base mutations by autosequence based on the Sanger method. The study used the chi square test and conditional logistic regression to compare the cases and controls. Identified mutations were compared to known myocilin mutations. Results: Unrelated 165 POAG patients and unaffected 173 controls enrolled for the study. The analysis revealed four variants of myocilin mutations in 49 participants which included one synonymous (silent) mutation (Thr474Thr; 45/338) and three missense mutations (Ala446Thr; 16/338), (Leu158Arg; 4/338) and (Arg342Lys; 1/338). The prevalence of myocilin (MYOC) gene mutations in this study was 14.5% (49/338). The study observed two previously reported mutations, Ala446Thr and Arg342Lys, as glaucoma causing mutations. The variant (Lys158Arg) observed in the study was a novel finding. These mutations were detected in age, sex and ethnically matched controls. The missense mutation, Ala446Thr, was found in eight cases and eight controls. Twenty (20) controls and 25 cases had the synonymous or silent (neutral) mutation, (Thr474Thr). Conclusions: The myocilin mutations represent a prevalence of 14.5 in a Zambian population. The Leu158Arg seems to represent novel glaucoma, causing missense mutation. Mutations in myocilin appear to play a big role in the pathogenesis of POAG in a Zambian population.