Inhibition of Shp2 Protein Eases Pulmonary Arterial Hypertension Symptoms in Rats, Study Reports
Treatment with Phps-1, which inhibits a protein called Shp2, was able to alleviate specific symptoms of pulmonary arterial hypertension (PAH) in a rat model, suggesting that Shp2 may be a potential therapeutic target for PAH treatment, a study reports.
The study, “Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats,” was recently published in BMC Pulmonary Medicine.
One of the major features of PAH is pulmonary vascular remodeling (PVR). PVR involves the thickening of the blood vessel wall, which is due, in part, to the over-proliferation of pulmonary vascular cells, one of the cell types lining the vessel. PVR leads to decreased blood flow through the vessels and contributes to pulmonary hypertension.
Researchers recently have begun exploring if specific receptor tyrosine kinase (RTK) inhibitors can treat PAH. Receptor tyrosine kinases are molecules that sit on the cell membrane and can relay information from outside the cell into the cell.
These molecules often promote cell proliferation and inhibit cell death. In this way, RTK inhibitors have been used to treat cancer.
In terms of PAH, Gleevec (imatinib), which is commonly used to treat chronic myeloid leukemia, was found to reverse PVR in an experimental animal model. Similarly, the multikinase inhibitor Nexavar (sorafenib) prevented PVR and improved cardiac function in another animal model of pulmonary hypertension.
Shp2, or Src homology 2 containing protein tyrosine phosphatase 2, is a protein that interacts with receptor tyrosine kinases, but its role in PAH is relatively unknown.
Using a rat model of PAH, researchers explored how the highly selective Shp2 inhibitor, Phps-1, affects PVR and ultimately PAH.
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After induction of PAH, the rats were treated with Phps-1 for 21 to 35 days. As expected, measures of PAH, including right ventricular systolic pressure and mean pulmonary arterial pressure, were elevated after PAH was induced.
Treatment with Phps-1 significantly reduced these measures, showing that inhibiting Shp2 could alleviate some of the symptoms of PAH.
By looking directly at the lung vascular tissue, the researchers saw that Phps-1 treatment reversed the fibrosis that developed after PAH induction, and could also reduce the thickness of the pulmonary arteries. In lung tissues from rats treated with the Shp2 inhibitor after PAH induction, levels of TGF-β — a molecule involved in fibrosis — were lower.
Cardiac function is also affected by PAH and results from an overgrowth of heart cells, called cardiomyocyte hypertrophy. By looking at the cardiomyocytes from rats treated with the Shp2 inhibitor, the researchers found that Phps-1 could also reduce PAH-induced hypertrophy.
In cell culture experiments, the researchers explored in more detail how inhibiting Shp2 could improve PVR. They showed that the beneficial effects of Shp2 inhibitor are, in part, due to its effects on the signaling molecules AKT and Stat3, inhibiting cell proliferation and cell migration.
“Shp2 is an important contributor to the development of PAH,” the researchers concluded. Future work will be needeed to validate these results before moving into human studies.
