Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress
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ABSTRACT:
PROVIDER: PRJNA953031 | ENA |
REPOSITORIES: ENA
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Project description:In our chemogenetic neurovacular mouse model, DRGs transcriptomic analysis was performed by RNA-seq; Oxidative stress is associated with cardiovascular and neurodegenerative disease. We created transgenic chemogenetic mouse lines expressing yeast D-amino oxidase (DAAO) in endothelial cells and neurons. DAAO generates hydrogen peroxide (H2O2) in target tissues when mice are provided with D-amino acids, causing oxidative stress. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. We provided these mice with D-alanine¬– expecting a vascular phenotype– but found that the mice develop sensory ataxia and neurodegeneration in dorsal root ganglia (DRG), associated with transgene expression within DRG neurons; electron microscopy revealed distorted mitochondria. DAAO-TGCdh5 mice also develop cardiac hypertrophy in response to chemogenetic oxidative stress, and we discovered transgene expression in parasympathetic nodose ganglia innervating the heart. We developed and characterized another transgenic line expressing DAAO under control of a different endothelial cell-specific Tie2 promoter. DAAO-TGTie2 mice express the transgene in endothelium but not neurons, and develop neither ataxia nor cardiac hypertrophy. The combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich's Ataxia. Our observations confirm that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy, and identify the DAAO-TGCdh5 mouse as a potentially informative animal model for Friedreich’s Ataxia.
2023-05-01 | GSE229143 | GEO
Project description:Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here we report studies of neurovascular oxidative stress in chemogenetic transgenic mouse lines expressing yeast D-amino acid oxidase (DAAO) in neurons and vascular endothelium. When these transgenic mice are fed D-amino acids, DAAO generates hydrogen peroxide in target tissues. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. When we provide these mice with D-alanine, they rapidly develop sensory ataxia caused by oxidative stress and mitochondrial dysfunction in neurons within dorsal root ganglia and nodose ganglia innervating the heart. DAAO-TGCdh5 mice also develop cardiac hypertrophy after chronic chemogenetic oxidative stress. This combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich's ataxia. Our observations indicate that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy. Studies of DAAO-TGCdh5 mice could provide mechanistic insights into Friedreich's ataxia.
| S-EPMC10227029 | biostudies-literature
Project description:Friedreich's ataxia (FRDA) is an autosomal-recessive neurodegenerative and cardiac disorder which occurs when transcription of the FXN gene is silenced due to an excessive expansion of GAA repeats into its first intron. Herein, we generate dorsal root ganglia organoids (DRGOs) by in vitro differentiation of human iPSCs. Bulk and single-cell RNA sequencing show that DRGOs present a close transcriptional signature with native DRGs and display the main peripheral sensory neuronal and glial cell subtypes. Furthermore, when co-cultured with human intrafusal muscle fibers, DRGO sensory neurons contact their peripheral targets and reconstitute the muscle spindle proprioceptive receptors. FRDA DRGOs recapitulate key molecular and cellular deficits of the disease that are extensively rescued only when the entire FXN intron 1 is removed and not with the excision of merely the expanded GAA tract. These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might be necessary to obtain a complete rescue of FXN expression and fully revert the pathological hallmarks of FRDA DRG neurons.
2020-07-27 | GSE148212 | GEO
Project description:Cysteine oxidative modification of cellular proteins is crucial for many aspects of cardiac hypertrophy development. However, integrated dissection of multiple types of cysteine oxidation proteome in cardiac hypertrophy is currently missing. Here we developed a novel discovery platform encompassing a customized biotin switch-based quantitative proteomics pipeline and an advanced analytic workflow to comprehensively profile the landscape of cysteine oxidation in ISO-induced cardiac hypertrophy mouse model. Specifically, we identified a total of 3,717 proteins containing 6,837 oxidized cysteine sites by at least one of reversible cysteine oxidation, cysteine sulfinylation (CysSO2H), and cysteine sulfonylation (CysSO3H). Analyzing the hypertrophy signatures that are reproducibly discovered from computational workflow highlighted a group of fatty acid beta-oxidation enzymes with a continual decreased temporal pattern and a significant decreased abundance in reversible oxidation with no temporal or abundance change in total cysteine, revealing the oxidative regulatory map of fatty acid metabolism in cardiac hypertrophy, which is featured by an overall reduced oxidative metabolism. Our cysteine oxidation platform depicts a dynamic and integrated landscape of the cysteine oxidative proteome, extracted molecular signature, and provided mechanistic insights in cardiac hypertrophy.
2018-08-29 | PXD010336 | Pride
Project description:The neurovascular unit, which includes neurons, glial cells, and vascular cells, plays crucial roles in the onset and progression of Alzheimer’s disease (AD). Therefore, effective drugs against AD should be able to target the multi-cellular neurovascular unit and the therapeutic relationships among neurovascular cells should be defined. We aimed to examine the therapeutic effects of an herbal remedy with multi-targeting capabilities, ukgansan (UGS), using in vitro models of AD, and to assess the similarity among neurovascular cells in terms of a therapeutic network.
2019-07-18 | GSE134414 | GEO
Project description:Friedreich’s ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal, but display a loss of motor coordination and cardiac abnormalities. Many ultimately succumb to heart failure. Administration of nicotinamide adenine dinucleotide (NAD+) precursors has shown promise in mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not “fail” per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of Friedreich’s Ataxia and warrant further investigation.
2024-08-28 | GSE271798 | GEO
Project description:We aimed to identify astroglial transcripts preferentially translated in the neurovascular unit. The translatome of whole astrocytes extracted following the bacTRAP protocol was compared to a translatome of astrocyte perivascular endfeet.
2017-01-27 | GSE72937 | GEO
Project description:Purpose: The physiological cardiac hypertrophy is an adaptive condition that does not associate with myocyte cell death while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. Alpha-2 macroglobulin (α-2M) an acute phase protein induces cardiac hypertrophy via the ERK1,2 and PI3K/Akt signaling. This study is aimed at exploring the miRNome of α-2M induced hypertrophied cardiomyocytes and to understand the role of miRNAs in determination of pathological and physiological hypertrophy. Methods: Hypertrophy was induced in H9c2 cardiomyoblasts using alpha-2 macroglobulin. The induction of hypertrophy is confirmed by microscopy and gene expression studies. Subsequently, the total RNA was isolated and small RNA sequencing was executed in Illumina HiSeq 2000. Results: Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy. Among the differentially expressed candidates, miR-99 family (miR-99a, miR-99b and miR-100) showed significant downregulation upon α-2M treatment while isoproterenol treatment (pathological hypertrophy) upregulated their expression. The binding site for Egr1 transcription factor was identified in the promoter region of miR-99 family, and interestingly all miRNAs with Egr1 binding site proven by ChIP-Seq were downregulated during physiological hypertrophy Conclusions: The results proved Egr-1 mediated regulation of miR-99 family determines the uniqueness of pathological and physiological hypertrophy. Upregulated miR-99 expression during pathological hypertrophy suggests that it can be a valuable diagnostic marker and potential therapeutic target for cardiac hypertrophy and heart failure. Small RNA profiles of control and hypertrophied cardiomyocyte H9c2 cells were generated by deep sequencing using Illumina HiSeq 2000
2015-11-01 | E-GEOD-73597 | biostudies-arrayexpress
Project description:The current study aims to investigate molecular alterations and biomarkers associated with partial BOO (PBOO) in rats. RNA-seq analyses were conducted to identify molecular alterations. Rats with PBOO experienced hypertrophy of smooth muscle cells and hyperplasia of interstitial cells during the first 4 weeks after the initiation of obstruction. Four weeks later, rats with PBOO showed activation of the adaptive immune response, cell death and apoptosis. The levels of BDNF and FGF2 in the serum gradually increased in the first four weeks and gradually decreased after week 4. FGF2 levels slightly correlated with prostate volume (R=0.156, P=0.0028) but not with age or BMI in BPH patients. FGF2 is involved in the development of hypertrophy in the PBOO bladder and shows a positive correlation with prostate volume in BPH patients.
2021-04-20 | GSE167430 | GEO
Project description:Purpose: The physiological cardiac hypertrophy is an adaptive condition that does not associate with myocyte cell death while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. Alpha-2 macroglobulin (α-2M) an acute phase protein induces cardiac hypertrophy via the ERK1,2 and PI3K/Akt signaling. This study is aimed at exploring the miRNome of α-2M induced hypertrophied cardiomyocytes and to understand the role of miRNAs in determination of pathological and physiological hypertrophy. Methods: Hypertrophy was induced in H9c2 cardiomyoblasts using alpha-2 macroglobulin. The induction of hypertrophy is confirmed by microscopy and gene expression studies. Subsequently, the total RNA was isolated and small RNA sequencing was executed in Illumina HiSeq 2000. Results: Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy. Among the differentially expressed candidates, miR-99 family (miR-99a, miR-99b and miR-100) showed significant downregulation upon α-2M treatment while isoproterenol treatment (pathological hypertrophy) upregulated their expression. The binding site for Egr1 transcription factor was identified in the promoter region of miR-99 family, and interestingly all miRNAs with Egr1 binding site proven by ChIP-Seq were downregulated during physiological hypertrophy Conclusions: The results proved Egr-1 mediated regulation of miR-99 family determines the uniqueness of pathological and physiological hypertrophy. Upregulated miR-99 expression during pathological hypertrophy suggests that it can be a valuable diagnostic marker and potential therapeutic target for cardiac hypertrophy and heart failure.
2015-11-01 | GSE73597 | GEO