Peroxynitrite is a novel risk factor and treatment target of glaucoma
Introduction
Elevated intraocular pressure (IOP) in glaucoma patients can result in progressive optic neuropathy and, if left untreated, irreversible blindness [1]. By 2040, the number of people suffering from glaucoma worldwide may increase to 111.8 million [2]. This figure is projected to 25.16 million in China By 2050 [3]. While primary open-angle glaucoma (POAG) is the more predominant form of glaucoma in Europeans and Africans, Asia accounts for about 86% of worldwide primary angle-closure glaucoma (PACG) cases, and China accounts for a vast majority (48%) of PACG in the world [2,4]. Nitric oxide (NO) is an important regulator of intraocular pressure; paradoxically, the same molecule is involved in the pathogenesis of PACG and POAG [[5], [6], [7], [8], [9], [10]]. NO can become highly damaging when it reacts with superoxide (O2•−) and forms much more powerful oxidant peroxynitrite (PN, ONOO−).
PN is much more reactive than NO or superoxide with a half-life of 10–20 ms. No other species has a long enough half-life to travel within and between cells and having the ability to break the DNA [11]. The DNA damge in turn activates DNA nick-sensing enzyme, mostly poly (ADP-ribose) polymerase-1 (PARP-1), which triggers the cleavage of NAD+ into nicotinamide and ADP-ribose and causes depletion of NAD+ and ATP resulting in cell dysfunction, necrosis or apoptosis. The cytotoxic effects of PN centering on the participation of PARP-1 and ADP-ribose have been implicated in the pathogenesis of a variety of diseases, including circulatory shock, sepsis and inflammation, injuries of the lung and the intestine [12]. Treatment with PARP inhibitors has produced protective effects in various diseases, including cancer [13,14].
PN causes nitration of various amino acid functional groups but mostly tyrosine and forms nitrotyrosine (NT) [15]. NT level is increased in eyes [16] and lungs [17] of caveolin 1 knockout (Cav1 KO) mice, which have ocular and pulmonary hypertension. This is consistent with increased NT expression in the cells of the trabecular meshwork (TM) specimens from patients with severe POAG [18]. In the retina, glutamate induced excessive formation of PN which causes apoptosis of retinal neurons [19]. Optic nerve histology revealed NT formation in damaged optic nerve heads of patients with glaucoma [20,21]. While PACG and POAG are considered to be focal diseases, evidence has emerged systemic factors are associated with the pathogenesis of glaucoma [22,23]. Cav1 is known to interact with endothelial nitric oxide synthase (eNOS), which is an important regulator of IOP, thus affecting NO production. When eNOS binds to Cav1, its activity is inhibited. Upon stimulation, the inhibitory clamp of Cav1 is relieved and NO production occurs.
Manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) is a metalloporphyrin that has a metal center Mn and a porphyrin ring, which serve as a PN decomposition catalyst. It is cell permeable and can attenuate the toxic effects of PN in vitro and in vivo. Treatment with MnTMPyP could reverse pulmonary hypertention in Cav1 Knockout mice [17]. Its protective effects in vivo are probably due to a combined antioxidant effect, involving superoxide dismutation and PN neutralization [24]. Based on the dual action of metalloporphyrins, the related compound MnTnBuOE-2-PyP5+has been in Phase I/II Clinical Trials on glioma patients (NCT02655601) as a radioprotector of normal brain [25].
This study aims to investigate the systemic NT level in PACG and POAG patients, and its association with the diseases. We hypothesize that systemic NT is a risk factor of POAG and PACG. Due to the short half-life and instability of PN, NT is used as a surrogate measure of PN, and the increased tyrosine nitration indicates the formation of PN.
Section snippets
Study participants and sample collection
Patients with PACG (n = 100) or POAG (n = 100) were consecutively recruited into this study between April 2017 and December 2017 from the Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Fudan University. And normal controls (n = 200) were consecutively recruited from subjects who participated in yearly health screenings during the study period. PACG and POAG were diagnosed following the International Society of Geographical and Epidemiological Ophthalmology (ISGEO). The
Baseline characteristics of PACG and POAG patients
Demographic features, biochemical indices, ocular parameters of PACG, and POAG patients are shown in Table 1. For patients who had glaucoma in both eyes, ocular parameters from the right eye were used. Most of the biomedical indices, including the level of total protein, were similar between glaucoma patients and control patients. UA was slightly lower in PACG patients (p = 0.049), TG (p = 0.013) and TB (p = 0.032) was higher in POAG patients compared with controls.
Increased serum NT in PACG and POAG patients
Serum NT levels were
Main findings
We find a significantly elevated serum NT levels in PACG and POAG patients compared to control subjects. Further, high serum NT levels are significantly associated with the increased risk of PACG and POAG. All patients enrolled in our study are glaucoma patients with onset of both eyes. The statistical effect of taking ocular parameters from right eye of patients is same as from one eye of patients randomly. At the same time, the error caused by the difference between the left eye and right
Financial Support
Supported by theShanghai Clinical Medical Center of Ocular Disease (2017ZZ01020, XHS, China), State Key Program of National Natural Science Foundation of China (81430007, XHS, China), the Funds for International Cooperation of Ministry of Science and Technology (20501100001809340, XHS, China), National Natural Science Foundation China (81100662, 81371015, YL, China), BrightFocus Foundation (G2018112, YL, USA), the 211 Proect of Fudan University (EHF158351, YL, China), Young Scientists Program
Declaration of competing interest
No conflicting relationship exists for any author.
Acknowledgments
The clinical specimen and information of glaucoma patients described in this manuscript were obtained from the eye bank of Eye and ENT Hospital of Fudan University. We would like to thank all the participants and the staffs for their valuable contribution to this research.
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Lifetime exposure of ambient PM<inf>2.5</inf> elevates intraocular pressure in young mice
2021, Ecotoxicology and Environmental SafetyCitation Excerpt :It can scavenge O2•− and catalyze ONOO- decomposition and detoxify ONOO- and reduce the formation of 3-NT (Ferrer-Sueta et al., 2002; Li et al., 2021a). Our previous study found that serum levels of 3-NT in PACG and POAG patients were significantly higher than controls and in outflow tissues of Cav1 KO mice, a glaucoma animal model with elevated IOP (Lei et al., 2020). Our previous study also found that MnTMPyP reversed IOP elevation induced by sustained use of NO donor (Hu et al., 2021).
Prolonged use of nitric oxide donor sodium nitroprusside induces ocular hypertension in mice
2021, Experimental Eye ResearchCitation Excerpt :It causes biological damages by oxidizing DNA and the nitration of tyrosine residues on protein (Batthyany et al., 2017; Szabo et al., 2007; Virag et al., 2003). Clinical studies from others and ourselves have shown that ONOO- is involved in the pathogenesis of POAG (Lei et al., 2020; Luthra et al., 2005; Okamoto et al., 2001; Sacca et al., 2007). In this study, our data indicated that the extended application of SNP formed ONOO-and caused nitrosative damage to the outflow tissue, which might be responsible for the IOP elevation.
A highly sensitive fluorescent probe RN-NA reveals peroxynitrite as a novel biomarker for primary open angle glaucoma
2024, International Journal of Ophthalmology
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Authorship note: YL, YTG, and MMS contributed equally to this work.