ABSTRACT
Glaucoma is an optic neuropathy in which the degeneration of retinal ganglion cells (RGCs) results in irreversible vison loss. Therefore, neuroprotection of RGCs from glaucomatous afflictions is crucial for glaucoma treatment. In this study, we aimed to investigate the beneficial effects of statins in the protection of RGCs using a rat model. Glaucomatous injury was induced in rats by chronic ocular hypertension (OHT) achieved after performing a circumlimbal suture. The rats were given either statins such as simvastatin and atorvastatin or a solvent weekly for 6 weeks. Retina sections underwent hematoxylin and eosin, Brn3a, or cleaved casepase-3 staining to evaluate RGC survival. In addition, modulation of glial activation was assessed. While the retinas without statin treatment exhibited increased RGC death due to chronic OHT, statins promoted the survival of RGCs and reduced apoptosis. Statins also suppressed chronic OHT-mediated glial activation in the retina. Our results demonstrate that statins exert neuroprotective effects in rat retinas exposed to chronic OHT, which may support the prospect of statins being a glaucoma treatment.
Subject(s)
Glaucoma/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Ocular Hypertension/drug therapy , Retinal Degeneration/drug therapy , Animals , Disease Models, Animal , Glaucoma/genetics , Glaucoma/pathology , Humans , Intraocular Pressure/drug effects , Neuroprotection/genetics , Neuroprotective Agents/pharmacology , Ocular Hypertension/genetics , Ocular Hypertension/pathology , Optic Nerve/drug effects , Optic Nerve/pathology , Optic Nerve Diseases/drug therapy , Optic Nerve Diseases/genetics , Optic Nerve Diseases/pathology , Rats , Retina/drug effects , Retina/pathology , Retinal Degeneration/genetics , Retinal Degeneration/pathology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/pathology , Transcription Factor Brn-3A/chemistry , Transcription Factor Brn-3A/isolation & purificationABSTRACT
Generation of autoantigens of nuclear origin, like dsDNA and extractable nuclear antigens (ENA) have largely been associated with dysregulated apoptosis and defective clearance of apoptotic debris in SLE. Heat shock protein (HSP) 27 has been reported to have anti-apoptotic properties hence it was of interest to study the expression of HSP27 and its regulatory molecule Brn3a and hsa-miR-939 in SLE patients with distinct autoantibodies specificities. SLE patients were categorized into three subsets based on their distinct sero-positivity for either anti-dsDNA antibody alone (anti-dsDNA(+) group) or anti-ENA antibody alone (anti-ENA(+) group) or both (anti-dsDNA(+) ENA(+) group). We investigated the mRNA and protein expression of HSP27 and Brn3a in peripheral blood leukocytes (PBLs) by real-time reverse transcriptase PCR and Western blotting. Expression of apoptosis markers caspase 3 and poly (ADP-ribose) polymerase (PARP) was determined by Western blotting. Hsa-miR-939 expression was determined using TaqMan(®) miRNA assay. In this study, we report significant downregulation of HSP27 in anti-ENA(+) patients and increased expression of caspase 3 and PARP in both anti-ENA(+) and anti-dsDNA(+) SLE subsets. A negative correlation was observed between the expression of HSP27 and apoptosis markers caspase 3 and PARP. Decreased Brn3a expression was observed in anti-ENA(+) SLE patients, which correlated positively with HSP27 expression. Expression of hsa-miR-939, which has a potential target site for Brn3a 3' UTR, was also elevated specifically in anti-ENA(+) patients. The decreased expressions of HSP27, Brn3a along with elevated levels of hsa-miR-939 are selectively associated with anti-ENA(+) patients and HSP27 was observed to be inversely associated with apoptosis. These findings are suggestive of distinct regulatory processes operative in SLE patient subsets with different autoantibody specificities.
Subject(s)
Autoantibodies/immunology , Gene Expression Regulation , HSP27 Heat-Shock Proteins/genetics , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Adolescent , Adult , Antibodies, Antinuclear/immunology , Case-Control Studies , Caspase 3/genetics , Caspase 3/metabolism , Enzyme Activation , Female , Gene Expression Profiling , HSP27 Heat-Shock Proteins/metabolism , Humans , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/metabolism , Male , MicroRNAs/chemistry , MicroRNAs/genetics , Middle Aged , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/metabolism , Transcription Factor Brn-3A/chemistry , Transcription Factor Brn-3A/genetics , Transcription Factor Brn-3A/metabolism , Young AdultABSTRACT
The Brn-3a POU family transcription factor is overexpressed in human cervical carcinoma biopsies and is able to activate expression of the human papilloma virus type 16 (HPV-16) upstream regulatory region (URR), which drives the expression of the E6 and E7 oncoproteins. Inhibition of Brn-3a expression in human cervical cancer cells inhibits HPV gene expression and reduces cellular growth and anchorage independence in vitro as well as the ability to form tumours in vivo. Here, we show that Brn-3a differentially regulates different HPV-16 variants that have previously been shown to be associated with different risks of progression to cervical carcinoma. In human cervical material, Brn-3a levels correlate directly with HPV E6 levels in individuals infected with a high risk variant of HPV-16, whereas this is not the case for a low-risk variant. Moreover, the URRs of high- and intermediate-risk variants are activated by Brn-3a in transfection assays, whereas the URR of a low-risk variant is not. The change of one or two bases in a low-risk variant URR to their equivalent in a higher-risk URR can render the URR responsive to Brn-3a and vice versa. These results help explain why the specific interplay between viral and cellular factors necessary for the progression to cervical carcinoma only occurs in a minority of those infected with HPV-16.
