Promising Treatment for Pulmonary Hypertension Unveiled

The Goncharova lab at UC Davis Health has validated a viable treatment for pulmonary hypertension. The illness is ultimately fatal, and there are currently no effective treatments available.

Restoring the functional growth suppressor tuberous sclerosis complex 2 (TSC2) may assist to reverse existing pulmonary vascular remodeling and pulmonary arterial hypertension, according to a study published in Science Signaling.

According to the American Lung Association, 500-1,000 new cases of pulmonary arterial hypertension are diagnosed in the United States each year.

When the small arteries in the lung thicken and narrow, this results in pulmonary hypertension. This reduces blood flow to the lungs, raising blood pressure and requiring the heart to work harder to pump blood. The heart gradually loses its ability to properly pump blood throughout the body.

“Pulmonary arterial hypertension is a rare and progressive disorder with a high mortality rate and no cure,” explained Elena A. Goncharova, professor of internal medicine and director of the Pulmonary Vascular Disease Program. “The condition is a serious public health problem with increasing death and hospitalization rates.”

Using TSC2 as a therapeutic intervention

Pulmonary hypertension is caused in part by the proliferation of pulmonary arterial vascular smooth muscle cells, which is produced by pulmonary artery stiffness.

The goal of the study was to determine if researchers could develop a mechanism to open small pulmonary arteries in order to selectively kill modified smooth muscle cells and correct pulmonary hypertension.

TSC2 is essentially nonexistent in vascular smooth muscle cells in tiny pulmonary arteries, according to the researchers. Furthermore, they discovered that TSC2 regulates cell development in response to mechanical biological signals, which means that if it is present, it can prevent pulmonary artery stiffening and remodeling.

“Ultimately, this discovery was more than we had hoped for. We realized by bringing back the growth suppressor TSC2, we could potentially return the arteries in the lung to a biological level.”—Elena A. Goncharova

The researchers then started looking into potential pharmaceutical options to restore functional TSC2 in pulmonary arterial vascular smooth muscle cells. Because TSC2 is regulated by the protein SIRT1, they tested the effect of the SIRT1 activator SRT2104, a drug that is currently in clinical trials as a therapeutic target in multiple age-related diseases.

“We found that treating pulmonary arterial vascular smooth muscle cells in rodents with SRT2104 significantly increased TSC2 protein levels, improving lung function and reducing pulmonary hypertension,” Goncharova said. “These results are very exciting and show that increasing TSC2 abundance could offer a new target for therapeutic intervention for a condition that is ultimately fatal and currently lacks effective treatments.”

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