Protein Shows Promise as a Therapeutic Target in Pulmonary Arterial Hypertension

October 25, 2010

October 25, 2010 (Montreal, Quebec City) — A protein implicated previously in leukemia, lymphomas, and prostate cancer might one day play a role in not only identifying individuals at risk for pulmonary arterial hypertension but also in their treatment, according to the results of a new study.

Dr Sébastien Bonnet

Researchers report that the oncoprotein kinase PIM-1 was expressed in the pulmonary artery smooth-muscle cells of individuals with the debilitating hypertension as well as in animal cells and that inhibiting PIM-1 in a rodent model reversed pulmonary hypertension.

Lead investigator Dr Sébastien Bonnet (Laval University, Quebec City) said the clinical implications of the research are important, given that there are currently no biomarkers to identify at-risk patients and no treatment options for patients with pulmonary arterial hypertension. "When the patient shows up in the hospital with pulmonary hypertension, he's going to die within five years, more or less," Bonnet told heartwire . "We believe we have identified a specific therapeutic target for pulmonary hypertension."

Presenting the results of the study here during the Canadian Cardiovascular Congress 2010, Bonnet, the recipient of the Canadian Cardiovascular Society's young investigator award, explained that the processes of pulmonary hypertension, such as arterial remodeling and increases in pressure, are related to the transcription factor NFAT, which is responsible for the activation of T-cells. As NFAT is not normally activated in healthy patients, the researchers wanted to understand the mechanism behind its activation in pulmonary arterial hypertension and to do so turned their attention to cancer research.

"In cancer, the cells have pretty much the same phenotype as those in pulmonary arterial hypertension, in that they proliferate and don't die," said Bonnet. "In cancer, we knew that PIM-1 activates NFAT and that if you block PIM-1, you block NFAT activation. We identified that, as in cancer, PIM-1 is expressed in patients with pulmonary hypertension. The good thing about PIM-1 is that it is not expressed anywhere else. If you don't have cancer and you don't have pulmonary hypertension, PIM-1 is almost not expressed. That's why it becomes a very interesting target."

Narrowed to Smooth-Muscle Cells

In one of their first experiments, the researchers measured levels of PIM-1 in the cells of individuals with pulmonary hypertension and determined that the oncoprotein was significantly increased compared with controls. Next, the researchers isolated specific cells, looking only at the lung arteries, to determine exactly where PIM-1 was expressed.

"We narrowed it down to only the pulmonary artery smooth-muscle cells, meaning that when you give PIM-1 inhibitors in patients with pulmonary hypertension, we're not going to affect the bronchi and the respiration system, but only the pulmonary arteries that are sick."

Next, in a rat model, the group showed that when treated with drugs designed to inhibit PIM-1, they were able to reverse pulmonary hypertension and "saved the animal," said Bonnet. Studies of PIM-1 knockout mice also showed that those without the protein were resistant to pulmonary arterial hypertension. To heartwire , Bonnet said his group also performed a small 50-person trial that addressed whether or not PIM-1 might work as a surrogate marker for pulmonary arterial hypertension by measuring PIM-1 levels in the blood. As noted, PIM-1 was expressed only in patients with pulmonary hypertension, leading researchers to expand the study to 2000 patients in order to test the validity of the biomarker in a larger population.

Next steps, he said, are to further test the PIM-1 inhibitors in other animals and eventually humans. He expects the process will take one to two years, barring any setbacks, for the drugs to be tested in the treatment of pulmonary arterial hypertension, for which there is currently little treatment, except for agents such as endothelin-receptor antagonists or phosphodiesterase type-5 inhibitors, such as sildenafil (Revatio, Pfizer), that attempt to alleviate symptoms and improve quality of life. The other option is a complete heart and lung transplant.


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