Could a novel drug target improve survival rates for patients with pulmonary hypertension?
Researchers have identified the gene FOXM1 as a promising target for the treatment of pulmonary hypertension, hoping to design drugs to reverse the vascular remodeling seen in these patients.
A recent study published in the American Journal of Respiratory and Critical Care Medicine has suggested the gene FOXM1 could be a promising target for treatment of pulmonary hypertension. The results are hoped to drive development of novel therapeutics to reverse a key feature of pulmonary hypertension, thickening of the lung artery walls.
Pulmonary hypertension, or high blood pressure affecting the arteries that supply blood to the lungs, is a severe lung disease that is known to damage the right side of the heart. The disease has an estimated five-year survival rate of 50%.
FOXM1 is known to control cell growth and has been indicated in cancer cell proliferation. In pre-clinical tests, the researchers at the Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago (IL, USA) were the first to establish the role of FOXM1 in pulmonary hypertension using a knock-out mouse model.
The studies of the gene highlighted the inability of the artery walls to thicken when the gene was knocked out.
"Currently we do not have drugs that target vascular remodeling in pulmonary hypertension," remarked lead author Zhiyu Dai, researcher at the Stanley Manne Children’s Research Institute and Research Assistant Professor at Northwestern University Feinberg School of Medicine (IL, USA).
"Our study shows that when we deleted the Foxm1 gene in the smooth muscle cells of the artery in mice, the result was thinner artery walls, reduced blood pressure in the lung and improved right heart function. We can use a compound against Foxm1 to reverse vascular remodeling in rat models of the disease."
The development of pulmonary hypertension is thought to be triggered by endothelial cell damage in the arteries, releasing growth factors to induce FOXM1 gene expression. This increases the production of smooth muscle cells in the middle layer of the artery wall, resulting in the artery wall thickening and causing high blood pressure in these vessels.
"We will now focus on developing new drugs that will inhibit the FOXM1 gene and hopefully improve outcomes for patients with pulmonary hypertension," Dai concluded.
Dai Z, Zhu MM, Peng Y, et al. Endothelial and smooth muscle cell interaction via FoxM1 signaling mediates vascular remodelling and pulmonary hypertension. Am. J. Resp. Crit. Care Med. (Epub ahead of print) doi: 10.1164/rccm.201709-1835OC (2018); www.luriechildrens.org/en/news-stories/study-identifies-new-target-for-treatment-of-pulmonary-hypertension/