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Endogenous Elevation of Homocysteine Induces Retinal Neuron Death in the Cystathionine-b-Synthase Mutant Mice

ABSTRACT: The effects of endogenous elevation of homocysteine on retinal gene expression were screened by microarray analysis, which was performed in triplicate (i.e., three different paired RNA samples) with RNA isolated from neural retinas of cbs+/- HM at 5-weeks after a methionine diet and age-matched wildtype mice. The microarray chips used in this study permitted the screening of 36,212 genes. Of particular interest were those genes in cbs+/- HM mice whose expression levels changed by at least a factor of 2 (increased or decreased expression) compared with the wild-type in each of the replicate experiments. Using these selection criteria, we identified 1219 genes. They were categorized into six functional groups: (1) proapoptosis, (2) antiapoptosis, (3) cell cycle, (4) antioxidant, (5) calcium signaling, and (6) axon growth/guidance, with the remaining genes with marked changes in expression placed in a miscellaneous group. After categorization, relevant genes were further narrowed by SAM analysis; q < 0.06 was considered significant.

ORGANISM(S): Mus musculus

PROVIDER: GSE56458 | GEO | 2014/04/04

SECONDARY ACCESSION(S): PRJNA243489

REPOSITORIES: GEO

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Endogenous Elevation of Homocysteine Induces Retinal Neuron Death in the Cystathionine-b-Synthase Mutant Mice

Project description:The effects of endogenous elevation of homocysteine on retinal gene expression were screened by microarray analysis, which was performed in triplicate (i.e., three different paired RNA samples) with RNA isolated from neural retinas of cbs+/- HM at 5-weeks after a methionine diet and age-matched wildtype mice. The microarray chips used in this study permitted the screening of 36,212 genes. Of particular interest were those genes in cbs+/- HM mice whose expression levels changed by at least a factor of 2 (increased or decreased expression) compared with the wild-type in each of the replicate experiments. Using these selection criteria, we identified 1219 genes. They were categorized into six functional groups: (1) proapoptosis, (2) antiapoptosis, (3) cell cycle, (4) antioxidant, (5) calcium signaling, and (6) axon growth/guidance, with the remaining genes with marked changes in expression placed in a miscellaneous group. After categorization, relevant genes were further narrowed by SAM analysis; q < 0.06 was considered significant. Microarrays were performed in triplicate as biological repeats and reverse fluoro (i.e., three different paired RNA samples) with RNA isolated from neural retinas of cbs+/- HM at 5-weeks after a methionine diet and age-matched wildtype mice after a methionine diet.

2014-04-04 | E-GEOD-56458 | biostudies-arrayexpress

Cystathionine-β-Synthase Promotes Colon Carcinogenesis

Project description:Purpose: The goal of this study is to investigate the role of CBS enzyme in colorectal carcinogenesis Methods: RNA-Seq transcriptome analysis of CBS-overexpression in NCM356 cels compared to control vector cells

2017-12-07 | GSE91000 | GEO

Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-beta-synthase mutant mouse.

Project description:To determine the effects of endogenous elevation of homocysteine on the retina using the cystathionine beta-synthase (cbs) mutant mouse.Retinal homocysteine in cbs mutant mice was measured by high-performance liquid chromatography (HPLC). Retinal cryosections from cbs(-/-) mice and cbs(+/-) mice were examined for histologic changes by light and electron microscopy. Morphometric analysis was performed on retinas of cbs(+/-) mice maintained on a high-methionine diet (cbs(+/-) HM). Changes in retinal gene expression were screened by microarray.HPLC analysis revealed an approximate twofold elevation in retinal homocysteine in cbs(+/-) mice and an approximate sevenfold elevation in cbs(-/-) mice. Distinct alterations in the ganglion, inner plexiform, inner nuclear, and epithelial layers were observed in retinas of cbs(-/-) and 1-year-old cbs(+/-) mice. Retinas of cbs(+/-) HM mice demonstrated an approximate 20% decrease in cells of the ganglion cell layer (GCL), which occurred as early as 5-weeks after onset of the HM diet. Microarray analysis revealed alterations in expression of several genes, including increased expression of Aven, Egr1, and Bat3 in retinas of cbs(+/-) HM mice.This study provides the first analysis of morphologic and molecular effects of endogenous elevations of retinal homocysteine in an in vivo model. Increased retinal homocysteine alters inner and outer retinal layers in cbs homozygous mice and older cbs heterozygous mice, and it primarily affects the cells of the GCL in younger heterozygous mice. Elevated retinal homocysteine alters expression of genes involved in endoplasmic reticular stress, N-methyl-d-aspartate (NMDA) receptor activation, cell cycle, and apoptosis.

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Cystathionine beta synthase (CBS) Over expression vs PLenti6 Expression Vector Human Bronchial Epithelial Cells (HBEC)

Project description:Cystathionine Beta Synthase (CBS), an enzyme that utilizes a methionine precursor to generate glutathione (GSSH), has been implicated in the mitigation of ROS production in COPD lung. Additionally, post-translational modification analysis on mouse and human cells treated with cigarette smoke showed the unique presence of mono- and di-methylated histone H3 lysine 27 that was not seen in controls, suggesting that cigarette smoke could lead to loss of Polycomb Repressive Complex 2 (PRC2) activity. To elucidate CBS as a potential upstream target for PRC2 inhibition, we overexpressed CBS in Human Bronchial Epithelial Cells (HBECs), grew them as 2D cultures, then conducted bulk RNA seq analysis.

2022-06-30 | GSE183858 | GEO

H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes.

Project description:Hydrogen sulfide (H2S), a cardioprotective gas, is endogenously produced from homocysteine by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE) enzymes. However, effect of H2S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesize that homocysteine and H2S regulate CBS and CSE expressions in a dose dependent manner in cardiomyocytes, and CBS deficiency induces cardiac CSE expression. To test the hypothesis, we treated murine atrial HL1 cardiomyocytes with increasing doses of homocysteine or Na2S/GYY4137, a H2S donor, and measured the levels of CBS and CSE. We found that homocysteine upregulates CSE but downregulates CBS whereas Na2S/GYY4137 downregulates CSE but upregulates CBS in a dose-dependent manner. Moreover, the Na2S-treatment downregulates specificity protein-1 (SP1), an inducer for CSE, and upregulates miR-133a that targets SP1 and inhibits cardiomyocytes hypertrophy. Conversely, in the homocysteine-treated cardiomyocytes, CBS and miR-133a were downregulated and hypertrophy was induced. In vivo studies using CBS+/-, a model for hyperhomocysteinemia, and sibling CBS+/+ control mice revealed that deficiency of CBS upregulates cardiac CSE, plausibly by inducing SP1. In conclusion, we revealed a novel mechanism for H2S-mediated regulation of homocysteine metabolism in cardiomyocytes, and a negative feedback regulation between CBS and CSE in the heart.

| S-EPMC5473925 | biostudies-literature

Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine β-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy

Project description:Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer’s disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine β-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H2S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H2S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H2S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.

2024-11-30 | PXD048079 | Pride

Elevated homocysteine is negatively correlated with plasma cystathionine β‐synthase activity in givosiran‐treated patients

Project description: Not available

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Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research.

Project description:Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H(2)S) through the transsulfuration pathway. H(2)S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine β-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H(2)S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (-/-) and heterozygous (+/-), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H(2)S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease.

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