Mutations in bone morphogenetic protein receptor type 2 results in altered adaptation to mechanical stress
A Llucia-Valldeperas, R Smal, F T Bekedam, T Neumann, M Ce, J Van Wezenbeek, A Vonk Noordegraaf, H J Bogaard, F S De ManAbstract
A mutation in the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) gene is in 70% of hereditary pulmonary arterial hypertension (PAH) patients the causative mutation. PAH is a rare disease that originates in the lungs but patients eventually die of right heart failure. Previous work demonstrated that right ventricular (RV) function is more impaired in patients carrying a BMPR2 mutation. However, the underlying mechanism remains elusive. We hypothesize that the BMPR2 mutation impairs the response to pressure overload leading to RV maladaptation.
Induced pluripotent stem cell (iPSCs) from 2 PAH patients BMPR2-mutation carriers and its isogenic controls (corrected BMPR2 mutation) were differentiated into ventricular cardiomyocytes (iPSC-CMs) and stretched 10% for 24h at 1Hz on the Flexcell FX-6000 system. Natriuretic peptides (NPPB and NPPA), along with genes involved in the processing of natriuretic peptides were quantified via RT-PCR. N-terminal Brain Natriuretic Peptides (NTproBNP) and Mid Regional proAtrial Natriuretic Peptides (MRproANP) secretions were measured on cell supernatants throughout specific immunoassays. Bulk RNA sequencing was performed to assess differences in gene expression between BMPR2-mutation carriers and isogenic controls upon stretching.
Upon stretch, both populations showed increased gene and protein expression of atrial and brain natriuretic peptides. Remarkably, BMPR2-mutation carriers presented higher baseline values for NTproBNP and MRproANP release compared to isogenic iPSC-CMs, despite a similar increase in both groups. Other genes involved in cardiac muscle tissue development did show differential expression between BMPR2-mutation carriers and isogenic iPSC-CMs upon stretching.
To conclude, BMPR2 is involved in the cardiac response to mechanical stretching. Experiments in atrial iPSC-CMs are currently ongoing to test potential differences in natriuretic peptide secretion between ventricular and atrial cardiomyocytes.