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  • Ovid Technologies (Wolters Kluwer Health)  (3)
  • Perros, Frederic  (3)
  • Sahoo, Susmita  (3)
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  • Ovid Technologies (Wolters Kluwer Health)  (3)
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  • 1
    Online Resource
    Online Resource
    Regulation of the Methylation and Expression Levels of the BMPR2 Gene by SIN3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Vol. 144, No. 1 ( 2021-07-06), p. 52-73
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. 1 ( 2021-07-06), p. 52-73
    Abstract: Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the BMPR2 (bone morphogenetic protein receptor type 2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of SIN3a (switch-independent 3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH. Methods: We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells. Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific adeno-associated virus serotype 1 or a lentivirus encoding for human SIN3a in vivo. Results: SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. It is interesting that we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. It is interesting that SIN3a overexpression inhibited human pulmonary arterial smooth muscle cells proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA-sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 (DNA methyltransferase 1) and EZH2 (enhancer of zeste 2 polycomb repressive complex 2) while promoting the expression of the DNA demethylase TET1 (ten-eleven translocation methylcytosine dioxygenase 1). Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF (CCCTC-binding factor) binding to the BMPR2 promoter. Last, we identified intratracheal delivery of adeno-associated virus serotype human SIN3a to be a beneficial therapeutic approach in PAH by attenuating pulmonary vascular and right ventricle remodeling, decreasing right ventricle systolic pressure and mean pulmonary arterial pressure, and restoring BMPR2 expression in rodent models of PAH. Conclusions: All together, our study unveiled the protective and beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in human pulmonary arterial smooth muscle cells. Our study also identified lung-targeted SIN3a gene therapy using adeno-associated virus serotype 1 as a new promising therapeutic strategy for treating patients with PAH.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.120.047978
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 10248: Regulation of the Methylation and Expression Levels of the Bmpr2 Gene by Sin3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Vol. 144, No. Suppl_1 ( 2021-11-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. Suppl_1 ( 2021-11-16)
    Abstract: Background: Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of Switch-Independent 3a (SIN3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH. Methods: We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells (hPASMC). Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific Adeno-Associated Virus serotype 1 (AAV1) or a lentivirus encoding for human SIN3a in vivo . Results: SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. Interestingly, we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. Interestingly, SIN3a overexpression inhibited hPASMC proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 and EZH2 while promoting the expression of the DNA demethylase TET1. Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF binding to the BMPR2 promoter. Finally, we identified intratracheal delivery of AAV1.hSIN3a to be a beneficial therapeutic approach in PAH- by attenuating pulmonary vascular and RV remodeling, decreasing RVSP and mPAP pressure, and restoring BMPR2 expression in rodent models of PAH. Conclusions: Altogether, our study unveiled the protective/beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in hPASMC.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.144.suppl_1.10248
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 13932: Lung-targeted Sin3a Gene Therapy as a Promising Strategy to Restore Bmpr2 Expression in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. Suppl_3 ( 2020-11-17)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
    Abstract: Background: Pulmonary arterial hypertension (PAH) is a fatal lung disease of multifactorial etiology, with no curative treatment. Several studies have previously suggested that hypermethylation of the BMPR2 promoter may be associated with gene repression and disease progression. However, the underlying mechanisms have yet to be discovered. Sin3A/B (Switch-Independent 3) plays a critical role in the transcriptional regulation of genes through various epigenetic mechanisms. Here, we investigated for the first time the role of SIN3a in the regulation of BMPR2 methylation and expression in PAH. Methods: Expression of SIN3a was analyzed by qRT-PCR and western blot in lung tissues from PAH patients and rodent models of PAH. Using a gain- and loss-of-function approach, we investigated the role of SIN3a on cell proliferation (BrdU assay) and migration (Boyden chamber assay), and BMPR2 levels in primary human pulmonary arterial smooth muscle cells (hPASMC) and endothelial cells (hPAEC). The methylation level was analyzed by MS-PCR. The therapeutic potential of SIN3a was tested in vivo in the Sugen/Hypoxia (SuHx) mouse and monocrotaline (MCT) rat models of PAH using an adeno-associated virus 1 encoding human SIN3a. Results: We found a significant downregulation of SIN3a expression in the lung samples from PAH patients, SuHx mice, and MCT rats. In hPASMC and hPAEC, our results showed that SIN3a inhibits cell proliferation, migration, and upregulates BMPR2 through two distinct pathways. In hPASMC, our data showed that SIN3a upregulates BMPR2 expression by inhibiting the methylation level of the BMPR2 promoter. In hPAEC, SIN3a restored BMPR2 expression independently of the methylation status by upregulating the FOXK2 transcription factor. In vivo , our results showed that restoring SIN3a expression by gene therapy significantly decreased MCT- and SuHx-induced PAH as illustrated by decreased vascular and RV remodeling, hypertrophy, PAP and RVSP. Conclusions: Altogether, our study revealed that SIN3a plays a critical role in the regulation of BMPR2 expression by modulating the lung epigenetic landscape. Additionally, our study identifies lung-targeted SIN3a gene therapy as a new promising therapeutic strategy for treating PAH patients.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.142.suppl_3.13932
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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