Surface Protein CD248 May Be Potential Therapeutic Target for PAH, Preclinical Study Suggests

Suppressing CD248, a cell surface protein, reduced pulmonary vascular remodeling — the key structural alteration in pulmonary arterial hypertension (PAH) — in a rat model of the disease.

CD248 was found to promote PAH-associated abnormal growth and migration of pulmonary artery smooth muscle cells (PASMCs), the cells that line the walls of pulmonary arteries, as well as oxidative stress.

Oxidative stress, a known contributor to PAH, is caused by an imbalance between the body’s production of potentially harmful reactive oxygen species (ROS) and its ability to detoxify them.

These findings suggest that blocking CD248 may be a new potential therapeutic strategy for PAH.

The study, “CD248 as a novel therapeutic target in pulmonary arterial hypertension,” was published in the journal Clinical and Translational Medicine.

PAH, a type of pulmonary hypertension, is characterized by the narrowing of the pulmonary arteries, restricting blood and oxygen flow and raising blood pressure (hypertension).

The arterial narrowing is caused by a process called pulmonary vascular remodeling, which involves the uncontrolled growth of PASMCs, progressively thickening the arterial walls. Such abnormal growth, along with a higher-than-normal ability to migrate, is associated with a switch in PASMCs’ state to a so-called synthetic phenotype.

While many of the underlying mechanisms of pulmonary vascular remodeling remain unclear, previous studies highlighted the involvement of a protein called platelet-derived growth factor (PDGF).

PDGF was found to promote PASMCs’ state switch and their abnormal growth, as well as oxidative stress. This increase in oxidative stress is associated with the activation of NOX4, an enzyme involved in the production of ROS and found at higher levels in PAH patients.

Now, researchers in China have identified a new potential therapeutic target — CD248 — to ease pulmonary vascular remodeling in PAH patients.

CD248, also known as endosialin or tumor endothelial marker 1, is a receptor protein found on the surface of cells developing from mesenchymal cells, such as muscle cells (including PASMCs).

Previous studies have shown that CD248 is involved in excessive cell growth in the context of cancer and diseases associated with abnormal tissue scarring, such as pulmonary fibrosis. Notably, researchers also found that the CD248 gene is mutated in some PAH patients.

In the current study, the team first found that CD248 levels were significantly and specifically increased in the PASMCs of a rat model of PAH, compared with healthy mice, and that these levels were associated with disease severity.

Further analyses in human PASMCs grown in the lab showed that blocking CD248 suppressed their switch to a synthetic phenotype, along with PDGF-induced growth and migration.

Moreover, the receptor was found to co-localize with PDGF at the cells’ surface and to be required for PDGF-associated signaling pathways. Data also showed that CD248 promoted oxidative stress by increasing the levels of NOX4 in human PASMCs.

Finally, suppressing CD248 in the lungs of a PAH rat model lessened disease severity and reduced pulmonary vascular wall thickness and PASMCs’ growth, “pointing out the relieved pulmonary vascular remodeling,” the researchers wrote.

CD248 blockage also resulted in a normalization of oxidative stress-associated pathways and NOX4 levels.

“This study provides the first evidence that CD248 contributes to pulmonary arterial hypertension,” the researchers wrote, noting that it induces “the increased proliferation and migration of PASMCs and shifts the balance toward a synthetic phenotype of PASMCs during disease progression.”

The results also highlighted that CD248 suppression “protects against the production of ROS and alleviates pulmonary vascular remodeling by interfering with PDGF signaling,” the team wrote.

Taken together, the findings suggest that CD248 may be a new therapeutic target for PAH. More studies are needed, however, to confirm the potential benefits of this type of therapeutic approach.