Enzyme Involved in Energy Production May Become New Target for Early Stage PH Therapy

A project investigating the role of a special protein called PFKFB3 in pulmonary hypertension (PH) has been awarded a $2.2 million grant from the National Heart, Lung and Blood Institute.

PFKFB3 is a potential new therapeutic target for early stages of PH. PFKFB3 is an enzyme involved in the process of breaking down glucose (a sugar) to use it as the energy source our cells require to work.

Environmental factors, such as smoking and air pollution, or genetic heart defects, can increase pressure inside the lungs and decrease the levels of oxygen – a condition called hypoxia and a known cause of PH.

In the early phases of hypoxia, the body responds with soaring levels of PFKFB3 particularly at the pulmonary artery, the main road carrying the blood coming from the heart into the lungs to be re-oxygenated. This response probably is a strategy to increase the energy levels of cells in the pulmonary artery to deal with the extra-work.

But the rise in PFKFB3 has detrimental effects, as it contributes to increasing even more the pressure inside lung blood vessels, while reducing the amount of blood they carry (the vessels become narrower, thicker). Patients become short of breath, dizzy, with swollen extremities and a racing pulse, which may culminate in heart failure.

“If you look at the X-ray or other lung image of a patient with pulmonary hypertension, you will see the vascular system is really, really reduced,” Yuqing Huo, director of the Vascular Inflammation Program at Medical College of Georgia (MCG)’s Vascular Biology Center, at Augusta University, said in a press release written by Toni Baker.

Previous work from the team found high levels of PFKFB3 in smooth muscle cells and endothelial cells of lung blood vessels in PH patients and disease animal models. Also, reducing the expression of PFKFB3 by half not only protected animals from PH, but also reduced inflammation and uncontrolled proliferation of cells in the animal’s pulmonary blood vessels.

These previous findings support the researchers’ hypothesis that the PFKFB3 enzyme plays a key role in the early stages of PH, making it a potential therapeutic target.

The grant will allow researchers to investigate an inhibitor of PFKFB3, and to study mice genetically engineered to have no enzyme expressed in lungs blood vessels.

The team also is particularly interested in understanding the link between PFKFB3 and inflammation, and will study its effects on different inflammatory mediators, such as a protein called NLRP3, or another called calpain. Damage to the lungs, such as those arising from cigarette smoke and air pollution exposure, trigger the release of growth factors that will activate calpain, leading to inflammation and detrimental remodeling in lungs’ vasculature.