Researchers demonstrated that point mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene led to a lower survival rate in pulmonary arterial hypertension (PAH), as published in Respiratory Research.

The experimental research conducted by Kabwe et al inserted a monoallelic single nucleotide in exon 1 of BMPR2 by using clustered regularly interspaced short palindromic repeats genome editing in a group of rats (named +/44insG rats) to compare them to wild-type rats. Both groups received an injection of monocrotaline (MCT) to induce PAH. Overall survival, pulmonary hypertension (PH), and pulmonary vascular disease (PVD) were assessed.

As expected, the mutation carriers had decreased BMPR2 lung signaling compared to the wild-type rats. One-week survival was significantly diminished in the +/44insG rats. These rats also exhibited an increased weight ratio of the right ventricle to left ventricle plus septum (RV/[LV+S]) and medial wall thickness in pulmonary arteries (PAs), as well as increased immature and decreased mature smooth muscle cells. Moreover, the PAs of the +/44insG rats responded poorly to prostaglandin-F2α- and endothelin-1-mediated contraction.


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A portion of the +/44insG rats also received tadalafil and displayed an even worse survival rate among all mutation carriers. The higher mortality could be attributed to higher RV/(LV+S) and medial wall thickness in distal arteries coupled with fibrosis noted in the myocardium of the right ventricle.

“The present study demonstrates that the Bmpr2 mutation promotes dedifferentiation of PA smooth muscle cells, late PVD and [right ventricular] myocardial fibrosis and adversely impacts both the natural and post-treatment courses of [monocrotaline]-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,” the authors said.

Along with these results, the successful creation of rats harboring a monoallelic mutation of the BMPR2 gene yields an important advance on its own. This will allow further research on hereditary PAH and potential novel targets. The BMPR2 mutation is the most important genetic risk factor for developing this disease, the authors said, and that patients who carry it experience a worse prognosis and earlier onset than those with idiopathic PAH.

Reference

Kabwe JC, Sawada H, Mitani Y, et al. CRISPR-mediated Bmpr2 point mutation exacerbates late pulmonary vasculopathy and reduces survival in rats with experimental pulmonary hypertension. Respir Res. 2022;23(1):87. doi:10.1186/s12931-022-02005-w