Researchers at the Max Planck Institute for Heart and Lung Research and Justus-Liebig University in Germany report that transcription factor FoxO1 regulates the division of cells and plays a key role in the development of pulmonary hypertension. The scientists, who were able to cure pulmonary hypertension in rats by activating FoxO1, believe their work could be used to develop a new treatment for the disease.
The researchers found an important clue about the central role of FoxO1 in tissue samples from pulmonary hypertension patients: “In these patients, FoxO1 is not sufficiently active, so that the activity of various genes is not properly controlled,” says Soni Savai Pullamsetti, Ph.D., who headed the project. “Experiments on cell cultures and rats have confirmed the results: If we switch off FoxO1 by means of genetic or pharmacological intervention, the vascular wall cells divide more frequently,” adds Rajkumar Savai, Ph.D., lead author of the study. Consequently, pulmonary hypertension develops.
In their study (“Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension”), published in Nature Medicine, the scientists also found that certain growth factors and chemical messengers are responsible for reduced FoxO1 activity.
“A potential new form of therapy could focus on increasing the activity of FoxO1 in the pulmonary arteries of patients,” notes Werner Seeger, M.D., department head at the Max Planck Institute in Bad Nauheim and director of Medical Unit II at Giessen University Hospital. This has already been demonstrated in experimental studies. Accordingly, pathological cell division in pulmonary vessel walls normalized when the researchers boosted FoxO1 activity. “Rats suffering from pulmonary hypertension were essentially cured,” says Dr. Seeger.
“Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo,” wrote the investigators. “Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.”
An estimated 100 million people worldwide suffer from pulmonary hypertension. The disease is characterized by progressive narrowing of the pulmonary arteries. The reduced diameter of the vessels leads to poor perfusion. The right ventricle tries to compensate by increasing its pumping action. This, in turn, increases the blood pressure in the pulmonary arteries. In the course of time, chronic overload damages the heart. The result is cardiac insufficiency, also known as congestive heart failure.
Several forms of treatment developed in recent years aim mainly to alleviate the symptoms and relieve strain on the heart. Pulmonary hypertension, however, is still incurable, not least of all due to insufficient knowledge of what causes the disease at the molecular level.
Based on their positive findings, the scientists are optimistic that the study findings can be used to develop a novel therapeutic approach.