IRF7 Gene Shows Potential as New Therapeutic Target in PH, Study Finds

Dialing up the activity of a gene called IRF7  may reduce pulmonary artery thickening, lower blood pressure, and ease inflammation in people with pulmonary hypertension (PH), a study using a rat model of the disease suggests.

The study, “Downregulation of Interferon regulatory factor 7 is link to pulmonary vascular smooth muscle cell proliferation and inflammation in Monocrotaline-induced pulmonary hypertension in rats,” was published in the journal Life Sciences.

IRF7 has been known to affect biological processes relevant to PH, such as inflammation, the migration of smooth muscle cells found in blood vessels, and apoptosis. Apoptosis refers to naturally “programmed” cell death in the body — as opposed to cell death caused by an injury — used to rid the body of cells that have been damaged beyond repair.

Given these effects, scientists from the First Affiliated Hospital of Guangxi Medical University, in China, hypothesized that a decrease, or downregulation, in IRF7 activity could promote the sort of vascular remodeling seen in PH. The team questioned whether restoring IRF7 activity would limit the disorder’s progression.

To test their hypothesis, the investigators used a rat model given monocrotaline (MCT), a common means of inducing PH in animals. In line with their thinking, the researchers found they could detect IRF7 protein and messenger RNA (mRNA) — the intermediate molecule in the generation of proteins from DNA — in smooth muscle cells of the pulmonary artery in control rats, while both IRF7 protein and mRNA were significantly decreased in those given MCT.

MCT-treated rats showed several characteristic signs of PH. These included high right ventricular systolic pressure (RVSP), a measure of the pressure inside the artery that supplies blood to the lungs; occluded, or blocked, small arteries; excessive vascular muscle tissue; right ventricular hypertrophy, or an enlargement of the heart’s right ventricle; and comparatively high levels of inflammatory molecules.

To test the effects of increasing IRF levels in MCT-treated rats, the researchers used a harmless adeno-associated virus (AAV) carrying Irf7, the rat equivalent of the human gene. This approach led to the overproduction of the IRF7 protein, which resulted in a reversal of disease-related changes in the rats’ pulmonary blood vessels.

Other benefits included an attenuated increase in RVSP, eased hypertrophy, and less alpha-SMA — a marker for smooth muscle tissue — suggesting a reduced severity of muscle buildup in the pulmonary arteries. Of note, an attenuated increase means that there was an increase in RVSP, but a lesser one than would have occurred if not using the viral vector.

In addition, the researchers found that higher levels of the IRF7 protein appeared to limit the degree of inflammation caused by MCT. In particular, the amounts of the inflammatory molecules TNF-alpha and interleukin-6 — both involved in muscle cell proliferation in the lungs — were lower upon treatment with the Irf-containing AAV vector.

Finally, smooth muscle cells in the pulmonary artery of AAV-treated rats showed less resistance to apoptosis, implying that they remained under the control of the body’s natural cellular maintenance mechanisms.

“The present results suggest that IRF7 may represent a novel potential therapeutic target for pharmacological or genetic interventions in PH,” the scientists wrote. “However, large scale preclinical studies in different PH models should be explored before further clinical studies.”