Targeting two proteins to prevent pulmonary hypertension

UIC researchers have identified two therapeutic targets for pulmonary arterial hypertension, an as-yet incurable disease that can be caused by a parasite laying eggs in the abdomen. The targets represent opportunity to diagnose, prevent and treat the life-threatening condition.

"I do expect that this research can lead to a better therapy and an early diagnostic approach for preventing the progression of this life-threatening disease and, of course, improving quality of life of the people in general," said lead author Suellen D'Arc dos Santos Oliveira, an assistant professor of anesthesiology, physiology and biophysics in the College of Medicine.

The human heart is divided into four chambers: two ventricles and two atria, each with its own purpose. The right ventricle pumps oxygen-depleted blood through our lungs, where it becomes oxygen-rich and ready to travel through the body.

Sometimes the arteries connecting our heart and lungs thicken, leaving less space for blood to flow. In response, the right ventricle beats harder and causes high blood pressure in the pulmonary arteries, a condition called pulmonary hypertension that can require a lung transplant or, in serious cases, be fatal.

Pulmonary arterial hypertension has various causes, but the most common is a tropical parasite called Schistosoma mansoni, which infects humans and rodents' blood vessels and lays eggs in their abdomen. From there, the eggs can migrate into other organs, like the lungs.

Schistosomiasis-associated pulmonary arterial hypertension is the most common form of Group I pulmonary hypertension, affecting more than 1 million people worldwide. Currently, there is no cure. While researchers have observed common traits in animals with pulmonary hypertension (such as more deaths and increased dysfunction in pulmonary blood cells and an imbalance in microorganisms in the lungs), the mechanisms behind this disease are poorly understood.

Oliveira and her team analyzed genetically modified mice exposed to Schistosoma mansoni eggs and patient-derived samples. With ultrasound imaging, microscopy and blood pressure tests, they examined the mice's hearts and lungs. They noticed an imbalance in two proteins: P2X7R, which can fuel inflammation and cell death, was present at higher levels; while c-IAP2, which helps prevent cell death, was present at lower levels.

Blocking P2X7R with a compound called brilliant blue G reduced some signs of the disease in mice, suggesting that this pathway deserves further study as a potential therapeutic target, according to Oliveira.

Oliveira said she'd like to expand this study to include more human samples.

"Of course, this is still a very initial step, and although we are super excited about the findings, I'm also very conscious of the need to perform larger translational studies," she said.

In addition to UIC faculty members, Oliveira's team comprises scientists from Rush University, the federal universities of São Paulo and Rio de Janeiro, Brazil; the Cleveland Clinic Foundation and Stanford University.

"To study a disease as complex as pulmonary hypertension, I feel it is very important that we don't get stuck in our individual research areas," Oliveira said. "Our team is a very interesting combination of pharmacologists, immunologists, pulmonologists, cardiologists and more. We have people working with every single aspect of this research."

UIC alum Elizabeth Villarreal began working with Oliveira as a second-year undergraduate. She's currently in her first year of Northwestern's Medical Scientist Training Program.

"It's been an amazing time from start to finish," she said. "Being a part of this lab not only provided me with an extraordinary community but also helped me find my passion in research. I've come to realize that research is difficult and can take a long time but ultimately is worth it because research like ours can help real people."