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Home > ARRA Stories > Combating Pulmonary Hypertension
Combating Pulmonary Hypertension

By Greg Borzo

Photo of Dr. Glenn Marsboom, Dr. Jalees Rehman, Dr. Stephen Archer and Dr. Peter Toth

From left to right: Glenn Marsboom, PhD, postdoctoral researcher; Jalees Rehman, MD, Assistant Professor, Department of Medicine/Section of Cardiology; Stephen Archer, MD, Harold Hines Jr. Professor of Medicine, Chief, Section of Cardiology and Principal Investigator; and Peter Toth, PhD, Section of Cardiology Research Associate/Assistant Professor (sitting). Photo by Lloyd DeGrane.

Pulmonary arterial hypertension (PAH) is a devastating disease caused by blockage of arteries in the lungs. It primarily affects young women, leading to disability and premature death, with a 15% mortality rate in the first year after diagnosis.

The blockage of arteries in PAH is caused by proliferating cells that grow too fast and don't die off, as they normally would. University of Chicago scientists studying PAH are not only finding cures for PAH and other forms of pulmonary hypertension, they are also gaining insights into the mechanism of cancer, which is also caused by uncontrolled cell growth.

"There's a growing recognition of common elements between pulmonary hypertension and cancer," said Stephen L. Archer MD, the Harold Hines Jr. Professor of Medicine in Cardiology at the University of Chicago.

The National Institutes of Health awarded $500,000 in ARRA funding to Archer and team for this year and the same amount for next year to continue their groundbreaking research aimed at developing a treatment for PAH.

Previously, Archer and colleagues built on research dealing with nitric oxide pathways in cells and pioneered the use of Viagra to treat pulmonary hypertension. Now the team has found a surprise: mitochondria play a role in causing PAH.

Mitochondria supply energy to cells and serve as their oxygen sensors. To function correctly they depend on a network, or mitochondrial matrix, along which chemicals flow. Normally, mitochondria form this network by rapidly joining and breaking apart (fusion and fission). This is accomplished with the help of mitofusion-2 as well as other proteins that help the mitochondria stick together in chains.

Archer and his colleagues have found that with PAH the mitochondria are structurally abnormal and unable to join together due, in part, to the loss of mitofusin-2.

They also discovered that PAH occurs when changes in the expression of key mitochondrial genes cause an inappropriate activation of hypoxia inducible factor (HIF), a protein that normally helps cells regulate oxygen levels. This overactivation of HIF sends a false "low-oxygen" signal to the cell, triggering inappropriate cell growth.

The new NIH grant will fund research aimed at understanding the role of HIF, mitofusin-2 and mitochondrial metabolism. The ultimate goal is to develop therapies that would inhibit the inappropriate activation of HIF and supplement the low level of mitofusin-2 in patients with PAH, thereby restoring normal mitochondrial form and function. This could improve or cure PAH.

Currently the researchers can supplement the mitofusion-2 through gene therapy. Soon they will study the potential of using a simple compound called dichloroacetate as a drug to accomplish the same thing. If this therapy works in animals, they will test the compound in humans.

This work was possible, Archer said, because of collaborators who run the University of Chicago's clinic for pulmonary hypertension, one of the country's largest such clinics. They include Mardi Gomberg-Maitland, MD, MSc, Associate Professor of Medicine and Director of the Pulmonary Hypertension Program; Stuart Rich, MD, Clinical Professor of Medicine; and Roberto Machado, MD, Department of Medicine. The intellectual input of scientific collaborators, including Jalees Rehman, MD, Department of Medicine, was also key.

"Only 10 in a million people acquire PAH, but hundreds of thousands suffer from other forms of pulmonary hypertension, often caused by heart failure or emphysema," Archer said. "Therefore, our research on PAH could have very broad applications with pulmonary hypertension and even cancer."

This article was originally published by the University of Chicago and written by Greg Borzo. Reposted with permission.

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