Hydrogen sulfide intervention in cystathionine-β-synthase mutant mouse helps restore ocular homeostasis

• 作者: Akash K.George Anwesha Laha Avisek Majumder Harpal S.SANDhu Mahavir Singh Naira Metreveli Rubens P.Homme Suresh C.Tyagi
• 来源期刊: 国际眼科杂志:英文版
• 学科: 医学
• 关键词: blood-retinal barrier integrity endoplasmic reticulum STRESS GLUTAMATE cytotoxicity inflammation oxidative STRESS mice
• 年，卷（期）: gjykzzywb_2019,（5）
• 页码范围: 754-764
• 页数: 11页
• 分类号: R771

摘要

AIM: To investigate the applications of hydrogen sulfide(H2 S) in eye-specific ailments in mice.METHODS: Heterozygous cystathionine-β-synthase(CBS+/-) and wild-type C57 BL/6 J(WT) mice fed with or without high methionine diet(HMD) were administered either phosphate buffered saline(PBS) or the slow-release H2 S donor: GYY4137. Several analyses were performed to study GYY4137 effects by examining retinal lysates for key protein expressions along with plasma glutamate and glutathione estimations. Intraocular pressure(IOP) was monitored during GYY4137 treatment;barium sulfate and bovine serum albumin conjugated fluorescein isothiocyanate(BSA-FITC) angiographies were performed for examining vasculature and its permeability post-treatment. Visionguided behavior was also tested employing novel object recognition test(NORT) and light-dark box test(LDBT) recordings.RESULTS: CBS deficiency(CBS+/-) coupled with HMD led disruption of methionine/homocysteine(Hcy) metabolism leading to hyperhomocysteinemia(HHcy) in CBS+/-mice as reflected by increased Hcy, and s-adenosylhomocysteine hydrolase(SAHH) levels. Unlike CBS, cystathionine-γ lyase(CSE), methylenetetrahydrofolate reductase(MTHFR) levels which were reduced but compensated by GYY4137intervention. Heightened oxidative and endoplasmic reticulum(ER) stress responses were mitigated by GYY4137 effects along with enhanced glutathione(GSH) levels. Increased glutamate levels in CBS+/-strain were prominent than WT mice and these mice also exhibited higher IOP that was lowered by GYY4137 treatment. CBS deficiency also resulted in vision-guided behavioral impairment as revealed by NORT and LDBT findings. Interestingly, GYY4137 was able to improve CBS+/-mice behavior together with lowering their glutamate levels. Blood-retinal barrier(BRB) appeared compromised in CBS+/-with vessels’ leakage that was mitigated in GYY4137 treated group. This corroborated the results for occludin(an integral plasma membrane protein of the cellular tight junctions) stabilization.CONCLUSION: Findings