Altered Expression Levels of MMP1, MMP9, MMP12, TIMP1, and IL-1βas a Risk Factor for the Elevated IOP and Optic Nerve Head Damage in the Primary Open-Angle Glaucoma Patients

Abstract

The aim of presented work was to analyze the impact of particular polymorphic changes in the promoter regions of the -1607 1G/2G MMP1, -1562 C/T MMP9, -82 A/G MMP12, -511 C/T IL-1β, and 372 T/C TIMP1 genes on their expression level in POAG patients. Blood and aqueous humor samples acquired from 50 patients with POAG and 50 control subjects were used for QPCR and protein levels analysis by ELISA. In vivo promoter activity assays were carried on HTM cells using dual luciferase assay. All studied subjects underwent ophthalmic examination, including BCVA, intraocular pressure, slit-lamp examination, gonioscopy, HRT, and OCT scans. Patients with POAG are characterized by an increased mRNA expression of MMP1, MMP9, MMP12, and IL-1β genes as compared to the control group (P < 0.001). Aqueous humor acquired from patients with POAG displayed increased protein expression of MMP1, MMP9, MMP12, and IL-1β compared to the control group (P < 0.001). Allele -1607 1G of MMP1 gene possesses only 42,91% of the -1607 2G allele transcriptional activity and allele -1562 C of MMP9 gene possesses only 21,86% of the -1562 T allele. Increased expression levels of metalloproteinases can be considered as a risk factor for the development of POAG.

Low‐dose rotenone exposure induces early senescence leading to late apoptotic signaling cascade in human trabecular meshwork (HTM) cell line: An in vitro glaucoma model

“…The extracellular matrix‐degrading MMP‐9 is known to play an important role in IOP maintenance (Robertson et al, ). A recent study has shown that expression of MMP‐9 mRNA in POAG patients is increased (Markiewicz et al, ). Thus, in this study, the upregulation of MMP‐9 is also an indicator of induction of glaucoma due to rotenone exposure of the HTM cells.…”

Microglia mediate non‐cell‐autonomous cell death of retinal ganglion cells

“…Because proinflammatory cytokines, including TNFα, interleukin-1β (IL-1β) and -6 (IL-6) have been reported to be increased in the aqueous humor of primary open-angle glaucoma (POAG) patients(Balaiya, Edwards, Tillis, Khetpal, & Chalam, 2011;Markiewicz et al, 2015;Ohira et al, 2015;Sawada, Fukuchi, Tanaka, & Abe, 2010), we investigated retinal expression of Tnfα, Il-1β, and Il-6 mRNAs and found that all of them were significantly upregulated at D1 (500-, 60-and 40-fold increases, respectively;Figure 6a-c). MC (MC, 100 μM, 5 μL/ eye) was topically applied every day to the eyes of mice.…”

“…The number of microglia increased by NMDA injection, which was attenuated by MC (n = 3-6, **p < .01 vs. control, ## p < .01 vs. NMDA, one-way ANOVA followed by Fisher's LSD test) [Color figure can be viewed at wileyonlinelibrary.com]3.6 | Microglia upregulate TNFα expression in response to NMDA injectionTo clarify molecular mechanisms involved in the neurotoxic effects of microglia, we analyzed temporal patterns of genes related to inflammatory responses. Because proinflammatory cytokines, including TNFα, interleukin-1β (IL-1β) and -6 (IL-6) have been reported to be increased in the aqueous humor of primary open-angle glaucoma (POAG) patients(Balaiya, Edwards, Tillis, Khetpal, & Chalam, 2011;Markiewicz et al, 2015;Ohira et al, 2015;Sawada, Fukuchi, Tanaka, & Abe, 2010), we investigated retinal expression of Tnfα, Il-1β, and Il-6…”

Genetic association of -1562C>T polymorphism in the MMP9 gene with primary glaucoma in a north Indian population

“…However none of the above mentioned studies included promoter region polymorphisms in the MMP9 , which therefore are not well investigated, both in POAG and PACG. rs3918242 is a C>T variant at position -1562 and affects the transcription of the gene; the CC genotype is associated with low promoter activity while CT, TT combinations exhibit higher activity [ 15 ]. The T substitution decreases the binding capacity of a putative transcription repressor protein, thereby causing an upregulation in the gene expression.…”

“…Among different MMPs, MMP9 encodes a 92-kDa multidomain zinc dependent enzyme known as gelatinase or type V collagenase and is known to extensively affect ECM deposition and turnover in the TM and LC regions in glaucoma [ 14 ]. Numerous studies have linked changes in the expression of MMP9 in the retina, optic nerve, aqueous humor, and TM with glaucomatous eyes in humans [ 15 – 17 ] and animal models of glaucoma [ 18 – 19 ]. The altered expression of MMPs could be a response to elevated IOP and simultaneously contribute to it by changing the outflow resistance.…”