Reduction of BMPR2 mRNA Expression in Peripheral Blood of Pulmonary Arterial Hypertension Patients: A Marker for Disease Severity?

Abstract

Pulmonary arterial hypertension (PAH) can be caused by pathogenic variants in the gene bone morphogenetic protein receptor 2 (BMPR2). While BMPR2 protein expression levels are known to be reduced in the lung tissue of heritable PAH (HPAH) patients, a systematic study evaluating expression in more easily accessible blood samples and its clinical relevance is lacking. Thus, we analyzed the BMPR2 mRNA expression in idiopathic/HPAH patients and healthy controls in blood by quantitative polymerase chain reaction and protein expression by enzyme-linked immunosorbent assay. Clinical parameters included right heart catherization, echocardiography, six-minute walking test and laboratory tests. BMPR2 variant-carriers (n = 23) showed significantly lower BMPR2 mRNA expression in comparison to non-carriers (n = 56) and healthy controls (n = 30; p < 0.0001). No difference in BMPR2 protein expression was detected. Lower BMPR2 mRNA expression correlated significantly with greater systolic pulmonary artery pressure and pulmonary vascular resistance. Higher BMPR2 mRNA expression correlated with greater glomerular filtration rate, cardiac index and six-minute walking distance. We demonstrated the feasibility to assess BMPR2 expression in blood and, for the first time, that BMPR2 mRNA expression levels are significantly reduced in variant carriers and correlated with clinical parameters. Further studies may evaluate the usefulness of BMPR2 mRNA expression in blood as a new marker for disease severity.

Is iron deficiency caused by BMPR2 mutations or dysfunction in pulmonary arterial hypertension patients?

“…For this study 79 patients with an invasively confirmed diagnosis of IPAH or HPAH and 30 healthy controls were prospectively recruited between May 2019 and January 2020. 12 All patients received an extended iron status assessment in addition to the routine diagnostic testing. The BMPR2 expression analysis and the cohort's clinical characteristics were described previously.…”

“…As previously reported, only BMPR2 mRNA in whole blood but not protein levels in serum were statistically significant reduced in mutation-carriers versus BMPR2 noncarriers. 12 Similar to the BMP ligands, inflammatory markers, such as IL6-levels or the C-reactive protein or the hypoxia-indicating marker erythropoietin did not correlate with serum hepcidin levels. By contrast, a strong positive correlation was observed in patients between serum hepcidin and ferritin (Pearson's correlation: 0.777, p < 0.0001; Figure 3), and a negative correlation with transferrin (p = 0.005), soluble transferrin receptor (p = 0.038), ferritin index (p = 0.002), and erythrocyte count (0.030) (Table 3).…”

“…Some information on this cohort has been published previously. 12 The ethics committees of the Medical Faculty of Heidelberg University Hospital, the Technical University of Dresden and the University of Leipzig had no objection against the conduct of the study (internal numbers: S-226/2019, EK 495112019, 414/19-lk, respectively). All participants provided written informed consent.…”

“…BMPR2 expression in whole blood was measured by quantitative polymerase chain reaction (qPCR) and ELISA as reported previously. 12 Serum was frozen at –80°C before analysis. QPCR measurements were performed as technical triplicates, ELISA measurements were carried out as technical duplicates.…”

“… 4 Another explanation could be related to the reduced BMPR‐II signaling in PAH patients. 11 , 12 BMPR‐II is expressed in hepatocytes, where it plays a critical role in activating hepcidin expression in response to bone morphogenetic protein 2 (BMP2) and BMP6 ligands. In healthy subjects binding of the ligand BMP6 to the BMP type one receptor ALK‐2 and the BMP type 2 receptor BMPR‐II leads to an increase in hepcidin gene expression.…”