Study suggests BMPER protein as treatment target in PAH
Researchers conducted experiments in cells, analyzed databases
Providing a protein called BMPER that is found at low levels in models of pulmonary arterial hypertension (PAH) may ease disease progression, a study suggests.
“Our study identifies BMPER as a novel therapeutic target for pulmonary arterial hypertension and provides new insights into the underlying mechanisms of the disease,” researchers wrote.
Through a series of experiments in cells and rodents, as well as analysis of genetic databases, researchers identified pathways by which low levels of BMPER, a protein released by cells lining blood vessels, cause structural alterations that are PAH hallmarks. Results also showed increasing BMPER may help normalize these pathways.
The study, “Targeting BMPER as a therapeutic strategy for pulmonary arterial hypertension,” was published in the journal Cellular Signaling.
Human dataset leads to study’s initial insight
In PAH, a process called vascular remodeling makes the pulmonary arteries narrow as the walls grow thicker due to smooth muscle cells. This increases blood pressure and the resistance to blood flow through the lungs and ultimately lowers blood oxygen throughout the body. Ultimately, this process can cause symptoms including shortness of breath and fatigue, and can lead to failure of the right ventricle, the chamber of the heart that pumps blood to the lungs.
Vascular remodeling involves changes in the function of endothelial cells, which line blood vessels, proliferation (higher number) of pulmonary arterial smooth muscle cells (PASMCs), and inflammation.
“Understanding these multifactorial processes is crucial for developing targeted therapeutic strategies aimed at halting or reversing the progression of PAH,” the researchers wrote.
To investigate these processes more closely, the team performed experiments in a variety of systems. Mice and rats provided two different models of PAH, caused by low oxygen exposure and exposure to a chemical called monocrotaline. Cell cultures of human pulmonary artery endothelial cells and smooth muscle cells were also conducted. In addition, the team analyzed a published dataset of gene activity in human pulmonary artery epithelial cells after reduced or normal oxygen exposure.
Understanding these multifactorial processes is crucial for developing targeted therapeutic strategies aimed at halting or reversing the progression of PAH.
This human dataset provided the study’s initial insight — that expression of BMPER, a regulator of blood vessel function, decreases significantly in human endothelial cells after exposure to low-oxygen conditions (hypoxia). Rat and mouse models mirrored this finding.
Results then showed hypoxia decreased levels of a different protein, called ERG, which in turn was associated with lower BMPER. The investigators also found the PI3K/AKT signaling pathway was overactive in response to hypoxia.
BMPER may offer new avenue for PAH treatment
Previous research showed BMPER can alter endothelial cell function by antagonizing a protein known as BMP4. In this study, adding BMPER to smooth muscle cells led to lower BMP4 protein levels in a dose-dependent manner. Increased BMP4 expression, or overexpression, resulted in proliferation and migration of smooth muscle cells, an effect that was blocked by BMPER overexpression. Notably, BMPER overexpression was achieved in rats through delivery of a viral vector to the windpipe.
“BMPER secreted by endothelial cells can influence the expression of BMP4 in PASMCs, thereby improving their proliferation and migration,” the team wrote. “This finding underscores the critical communication between endothelial cells and smooth muscle cells, suggesting BMPER may serve as a regulatory factor in the vascular response to injury or stress.”
The findings further showed BMPER eased cell proliferation and migration in endothelial cells by inhibiting the PI3K/AKT pathway. BMPER overexpression also resulted in thinner right ventricular walls and a reduced enlargement of the heart muscle.
Together, these results “highlight BMPER’s multifaceted role in vascular remodeling within the context of PAH,” according to the researchers. “In conclusion, targeting BMPER may provide a new avenue for therapeutic intervention in PAH, warranting further investigation into its mechanisms and potential applications in clinical settings. The interplay between BMPER and BMP4 represents a pivotal area for future research, potentially informing more effective treatments for patients suffering from this debilitating condition.”
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