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Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE229143 | GEO | 2023/05/01

REPOSITORIES: GEO

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Project description:To investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure, a tetracycline-regulated transgenic system to conditionally switch a constitutively-active form of the Akt1 protein kinase on or off in the adult heart was developed. Short-term activation (2 weeks) of Akt1 resulted in completely reversible hypertrophy with maintained contractility. In contrast, chronic Akt1 activation (6 weeks) induced extensive cardiac hypertrophy, severe contractile dysfunction, and massive interstitial fibrosis. The focus of this study was to create a transcript expression profile of the heart as it undergoes reversible Akt1-mediated hypertrophy and during the transition from compensated hypertrophy to heart failure. Heart tissue was analyzed before transgene induction, 2 weeks after transgene induction, 2 weeks of transgene induction followed by 2 days of repression, 6 weeks after transgene induction and 6 weeks of transgene induction followed by 2 weeks of repression. Acute over expression of Akt1 (2 weeks) leads to changes in the expression of 826 transcripts relative to non-induced hearts, whereas chronic induction (6 weeks) led to changes in the expression of 1611, of which 65% represented transcripts that were regulated during the pathological phase of heart growth. Another set of genes identified were uniquely regulated during heart regression but not growth, indicating that non-overlapping transcription programs participate in the processes of cardiac hypertrophy and atrophy. These data define the gene regulatory programs downstream of Akt that control heart size and contribute to the transition from compensatory hypertrophy to heart failure. Experiment Overall Design: Gene expression data from DTG-positive mouse hearts were examined before the induction of the transgene Akt1 (time point 1), 2 weeks after the induction of the transgene Akt1(time point 2), 2 weeks after the induction of the transgene Akt1 and 2 days after the repression of the transgene Akt1 (time point 3), 6 weeks after the induction of the transgene Akt1(time point 4) and 6 weeks after the induction of the transgene Akt1 and 2 weeks after the repression of the transgene Akt1 (time point 5). N = 3 to 4 sets of independent hybridizations from individual mice were performed for each time point.

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Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress

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