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Respiratory Research
Published in: Respiratory Research 1/2022

01-12-2022 | Tadalafile | Research

CRISPR-mediated Bmpr2 point mutation exacerbates late pulmonary vasculopathy and reduces survival in rats with experimental pulmonary hypertension

Authors: Jane Chanda Kabwe, Hirofumi Sawada, Yoshihide Mitani, Hironori Oshita, Naoki Tsuboya, Erquan Zhang, Junko Maruyama, Yoshiki Miyasaka, Hideyoshi Ko, Kazunobu Oya, Hiromasa Ito, Noriko Yodoya, Shoichiro Otsuki, Hiroyuki Ohashi, Ryuji Okamoto, Kaoru Dohi, Yuhei Nishimura, Tomoji Mashimo, Masahiro Hirayama, Kazuo Maruyama

Published in: Respiratory Research | Issue 1/2022

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Abstract

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.
Appendix
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Metadata
Title
CRISPR-mediated Bmpr2 point mutation exacerbates late pulmonary vasculopathy and reduces survival in rats with experimental pulmonary hypertension
Authors
Jane Chanda Kabwe
Hirofumi Sawada
Yoshihide Mitani
Hironori Oshita
Naoki Tsuboya
Erquan Zhang
Junko Maruyama
Yoshiki Miyasaka
Hideyoshi Ko
Kazunobu Oya
Hiromasa Ito
Noriko Yodoya
Shoichiro Otsuki
Hiroyuki Ohashi
Ryuji Okamoto
Kaoru Dohi
Yuhei Nishimura
Tomoji Mashimo
Masahiro Hirayama
Kazuo Maruyama
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-022-02005-w

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