Reversing a disease: FOXF1 fixes Pulmonary Arterial Hypertension

by Adrienne Mueller, PhD
December 13, 2023

Pulmonary arterial hypertension (PAH) is a debilitating disease that worsens over time; ultimately leading to right heart failure and death. PAH is caused by dysfunction of cells in our lung arteries called endothelial cells. Previous studies have shown that lung endothelial cell dysfunction in PAH is related to DNA damage not being repaired. In a recent study led by Sarasa Isobe, MD, PhD, and BASE Director Marlene Rabinovitch, MD and published in Nature Communications, investigators identified the mechanisms underlying PAH-related unrepaired DNA damage in lung endothelial  cells.

Because the protein BMPR2 is known to be related to PAH, the team first validated that endothelialcells without BMPR2 also show reduced DNA repair. The investigators then identified which other proteins had faulty expression patterns in BMPR2-lacking lung endothelial. They found reduced expression of a protein called FOXF1, a protein known to be selectively present in lung endothelial cells. FOXF1 is also a transcription factor: a protein that regulates the expression of other proteins. When the team reduced FOXF1 directly in lung endothelial cells - as opposed to by proxy via loss of BMPR2 - they found that endothelial cells again had DNA damage and impaired cellular repair. The investigators then took their study a step further by showing that transfection of FOXF1 into lung cells with PAH repairs the DNA damage and restores cell growth and repair. Finally the investigators went from in vitro to in vivo and delivered FOXF1 directly to mice with BMPR2-related PAH - and they reversed the disease.

Isobe et al’s findings not only reveal the mechanism by which BMPR2 affects lung endothelial cells in PAH, but also show that restoration of normal FOXF1 levels can rescue the disease. FOXF1 is expressed selectively in lung epithelial cells and it is therefore a promising new candidate for developing PAH therapies.

Restoring Foxf1 to lung endothelial cells of subjects with PAH by way of adeno-associated virus (AAV) reverses Pulmonary Arterial Hypertension (PAH).

Additional Stanford Cardiovascular Institute-affiliated investigators who contributed to this study include , Ramesh V. Nair, Helen Y. Kang, Lingli Wang, Jan-Renier Moonen, Tsutomu Shinohara, Aiqin Cao, Shalina Taylor, Shoichiro Otsuki, David P. Marciano, Rebecca L. Harper, Mir S. Adil, Chongyang Zhang, Mauro Lago-Docampo, Jesse M. Engreitz, and Michael P. Snyder.

Dr. Sarasa Isobe

Dr. Marlene Rabinovitch