HDAC9 Complex Inhibition Improves Smooth Muscle Dependent Arterial Stenosis
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ABSTRACT:
PROVIDER: PRJNA492933 | ENA |
REPOSITORIES: ENA
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Project description:Patients with heterozygous missense mutations in the ACTA2 or MYH11 genes are known to exhibit thoracic aortic aneurysm (TAA) and a risk of early onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Recently an epigenetic complex containing the histone deacetylase HDAC9 and the long noncoding RNA, MALAT1 was implicated in pathologic vascular smooth muscle cell phenotypic changes in aneurysmal disease, however its involvement in stenotic disease has not been explored. Herein we implicate the HDAC9-MALAT1 complex in transcriptional silencing of contractile associated gene products, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in Hdac9 or Malat1 deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 reduced neointimal formation. In conclusion, we report the implication of the HDAC9-MALAT1 complex in stenotic disease and demonstrate that pharmacologic therapy based on epigenetic targets can ameliorate arterial obstruction in an experimental system.
2021-09-01 | GSE120394 | GEO
Project description:Chronic biomechanical stress elicits remodeling of the arterial wall and causes detrimental arterial stenosis and stiffening. In this context, molecular determinants controlling proliferation and stress responses of vascular smooth muscle cells (VSMCs) have been insufficiently studied. We identified the transcription factor ‘nuclear factor of activated T-cells 5’ (NFAT5) as crucial regulatory element of mechanical stress responses of VSMCs. The relevance of this observation for biomechanically induced arterial remodeling was investigated in mice upon SMC-specific knockdown of NFAT5. While blood pressure levels, vascular architecture and flow-induced collateral growth were not affected in these mice, both hypertension-mediated arterial thickening and muscularization of pulmonary arteries during pulmonary artery hypertension (PAH) were impaired. In all models, a decrease in VSMC proliferation was observed indicating that NFAT5 controls activation of VSMCs in the remodeling arterial wall. Mechanistically, mechanoactivation of VSMCs promotes nuclear translocation NFTA5c upon its phosphorylation at Y143 and dephosphorylation at S1197. As evidenced by transcriptome studies, loss of NFAT5 in mechanoactivated VSMCs impairs expression of gene products controlling cell cycle and transcription/translation. These findings identify NFAT5 as molecular determinant of VSMC responses to biomechanical stress and arterial thickening.
2018-08-10 | GSE106274 | GEO
Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of ?-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. microRNA expression profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed. Pulmonary arterial smooth muscle cells were harvested form 3 mice.
2014-01-22 | E-GEOD-42015 | biostudies-arrayexpress
Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of α-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. Transcriptional profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed. Pulmonary arterial smooth muscle cells were harvested from 3 mice.
2014-01-22 | E-GEOD-42014 | biostudies-arrayexpress
Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of α-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. microRNA expression profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed.
2014-01-22 | GSE42015 | GEO
Project description:NOX1 is a catalytic subunit of nonphagocytic NADPH oxidase, mainly localized to smooth muscle cells in the vasculature. We investigated the pathology underlying the pulmonary arterial hypertension-like phenotype demonstrated in mice deficient in the Nox1 gene (Nox1-KO). Spontaneous enlargement and hypertrophy of the right ventricle, accompanied by hypertrophy of pulmonary vessels, were demonstrated in Nox1-KO at 9-18 weeks of age. Since an increased number of α-smooth muscle actin-positive vessels was observed in Nox1-KO, pulmonary arterial smooth muscle cells (PASMCs) were isolated and characterized by flow cytometry and TUNEL staining. In Nox1-/Y PASMC, the number of apoptotic cells was significantly reduced without any change in the expression of endothelin-1, and hypoxia-inducible factors HIF-1a and HIF-2a, factors implicated in the pathogenesis of PAH. Transcriptional profiling of mouse pulmonary arterial smooth muscle cells in wild-type and NOX1-KO was analyzed.
2014-01-22 | GSE42014 | GEO
Project description:DNA methylation signatures of pulmonary arterial smooth muscle cells in chronic thromboembolic pulmonary hypertension
2018-04-13 | GSE113061 | GEO
Project description:Our objective is to identify new miRNAs and their target mRNAs involved in arterial stenosis, especially pathological changes of smooth muscle cells. To this end, the balloon injury model was used to induce the activation of smooth muscle cells by damaging arterial endothelial cells. The balloon-injured rat carotid arteries were isolated and subjected to the RNA-Seq.
2022-10-01 | E-MTAB-11100 | biostudies-arrayexpress
Project description:We analyze the protein-RNA interactions of HDAC9 and BRG1 in human aortic smooth muscle cells overexpressing mutant aneurysm alleles (TGFBR2G357W and ACTA2R179H) and wild-type cells using CLIP-seq.
2018-01-13 | GSE93744 | GEO
Project description:Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration. RNAseq on innervated and 3 day denervated adult soleus muscle from wildtype mice is compared with that from 3 day denervated soleus muscle from Dach2/Hdac9 deleted mice to identify Dach2/Hdac9-regulated genes.
2015-10-29 | E-GEOD-58669 | biostudies-arrayexpress