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CRISPR-mediated Bmpr2 point mutation exacerbates late pulmonary vasculopathy and reduces survival in rats with experimental pulmonary hypertension
http://hdl.handle.net/10076/00021057
http://hdl.handle.net/10076/0002105797efdffe-accc-4928-b774-9a2c2fb27b60
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
2022DM0914 (2.9 MB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||
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| 公開日 | 2023-03-28 | |||||||
| タイトル | ||||||||
| タイトル | CRISPR-mediated Bmpr2 point mutation exacerbates late pulmonary vasculopathy and reduces survival in rats with experimental pulmonary hypertension | |||||||
| 言語 | en | |||||||
| 言語 | ||||||||
| 言語 | eng | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Pulmonary hypertension | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Survival | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Rats | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Genome editing | |||||||
| キーワード | ||||||||
| 主題Scheme | Other | |||||||
| 主題 | Animal model | |||||||
| 資源タイプ | ||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||
| 資源タイプ | doctoral thesis | |||||||
| アクセス権 | ||||||||
| アクセス権 | open access | |||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||
| 著者 |
JANE, CHANDA KABWE
× JANE, CHANDA KABWE
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| 著者（ヨミ） | ||||||||
| 姓名 | ジェーン, チャンダ カブウェ | |||||||
| 言語 | ja | |||||||
| 抄録 | ||||||||
| 内容記述タイプ | Abstract | |||||||
| 内容記述 | Background: Patients with pulmonary arterial hypertension (PAH) carrying bone morphogenetic protein receptor type 2 (Bmpr2) mutations present earlier with severe hemodynamic compromise and have poorer survival outcomes than those without mutation. The mechanism underlying the worsening clinical phenotype of PAH with Bmpr2 mutations has been largely unaddressed in rat models of pulmonary hypertension (PH) because of the difficulty in reproducing progressive PH in mice and genetic modification in rats. We tested whether a clinically-relevant Bmpr2 mutation affects the progressive features of monocrotaline (MCT) induced-PH in rats. Methods: A monoallelic single nucleotide insertion in exon 1 of Bmpr2 (+/44insG) was generated in rats using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9, then PH, pulmonary vascular disease (PVD) and survival after MCT injection with or without a phosphodiesterase type 5 inhibitor, tadalafil, administration were assessed. Results: The +/44insG rats had reduced BMPR2 signalling in the lungs compared with wild-type. PH and PVD assessed at 3-weeks after MCT injection were similar in wild-type and +/44insG rats. However, survival at 4-weeks after MCT injection was significantly reduced in +/44insG rats. Among the rats surviving at 4-weeks after MCT administration, +/44insG rats had increased weight ratio of right ventricle to left ventricle plus septum (RV/[LV + S]) and % medial wall thickness (MWT) in pulmonary arteries (PAs). Immunohistochemical analysis showed increased vessels with Ki67-positive cells in the lungs, decreased mature and increased immature smooth muscle cell phenotype markers in the PAs in +/44insG rats compared with wild-type at 3-weeks after MCT injection. Contraction of PA in response to prostaglandin-F2α and endothelin-1 were significantly reduced in the +/44insG rats. The +/44insG rats that had received tadalafil had a worse survival with a significant increase in RV/(LV + S), %MWT in distal PAs and RV myocardial fibrosis compared with wild-type. Conclusions: The present study demonstrates that the Bmpr2 mutation promotes dedifferentiation of PA smooth muscle cells, late PVD and RV myocardial fibrosis and adversely impacts both the natural and post-treatment courses of MCT-PH in rats with significant effects only in the late stages and warrants preclinical studies using this new genetic model to optimize treatment outcomes of heritable PAH. |
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| 言語 | en | |||||||
| 内容記述 | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | 本文/The Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, 2‑174 Edobashi, Tsu city, Mie 514‑8507, Japan | |||||||
| 内容記述 | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | 22p | |||||||
| 書誌情報 |
発行日 2022-09-21 |
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| DOI | ||||||||
| 識別子タイプ | DOI | |||||||
| 関連識別子 | 10.1186/s12931-022-02005-w | |||||||
| フォーマット | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | application/pdf | |||||||
| 著者版フラグ | ||||||||
| 出版タイプ | VoR | |||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||
| 出版者 | ||||||||
| 出版者 | 三重大学 | |||||||
| 出版者（ヨミ） | ||||||||
| ミエダイガク | ||||||||
| 学位名 | ||||||||
| 学位名 | 博士(医学) | |||||||
| 学位授与機関 | ||||||||
| 学位授与機関識別子Scheme | kakenhi | |||||||
| 学位授与機関識別子 | 14101 | |||||||
| 学位授与機関名 | 三重大学 | |||||||
| 学位授与年月日 | ||||||||
| 学位授与年月日 | 2022-09-21 | |||||||
| 学位授与番号 | ||||||||
| 学位授与番号 | 甲医学第2153号 | |||||||
| ノート | ||||||||
| 資源タイプ（三重大） | ||||||||
| Doctoral Dissertation / 博士論文 | ||||||||
