Dr. Sébastien Bonnet

Professor, Faculty of Medicine Canada Research Chair in Vascular Biology Laval University
Researcher of the month: 
Dec 2010

There is a good reason why Dr. Sébastien Bonnet, a Laval University researcher, received the Canadian Cardiovascular Society’s Young Investigator’s Award, Basic Science, and Hypertension Canada’s New Investigator’s Award in 2010 for his outstanding work in the field of pulmonary hypertension.

Bonnet and his team of researchers at Laval University in Quebec, QC, have identified an early biomarker for pulmonary arterial hypertension (PAH). The biomarker, an oncoprotein called PIM-1, can be detected in patients with PAH by a simple blood test.

Until now, this lethal disease had no biomarker at all. PAH could only be detected in the later stages, once enough arterial damage had occurred to cause debilitating symptoms. To be diagnosed, patients with PAH had to undergo a number of expensive and time-consuming tests, including ultrasound, invasive catheterization, MRI, angiography, or a 6-minute walk test. Many patients are too sick to endure these procedures.

The discovery may have far-reaching clinical implications for these patients. It means that PAH can be diagnosed and treated earlier. Bonnet hopes that treating patients with PAH at an earlier stage may improve their quality of life and perhaps even prolong their survival. 

 Bonnet and his team believe that PIM-1 is present in pulmonary arteries at the very beginning of the disease process. “We believe that this protein is expressed only when smooth muscle cells in pulmonary arteries start to get sick,” he says.

His team has correlated the expression of PIM-1 in diseased pulmonary arteries and blood with the severity of PAH in a small clinical trial of 50 patients. “That’s why we believe that the expression of PIM-1 is a good biomarker of PAH.”

Bonnet hopes to put the biomarker to the test in a larger clinical trial of at least 2,000 patients with PAH in the next 2 years. “Our goal is to demonstrate that there’s a good correlation between circulating PIM-1 and the severity of PAH.”

Finding the origin of PAH

Bonnet’s laboratory is also the first and only research facility in Canada to focus on identifying whether the misregulation or misfunctioning of microRNAs (miRNAs) is responsible for the origin of PAH. These microscopic fragments of RNA regulate one of the first steps in protein manufacture within the human body.

Bonnet’s team stumbled on the important role that miRNAs play in PAH, while investigating the mechanisms that lead to the expression of PIM-1 in diseased pulmonary arteries.

“We believe that we’ve made a major breakthrough in understanding the genetic and molecular mechanisms of PAH in humans,” he says.

Studies at his laboratory have shown that growth factors and circulating vasoactive agents that are commonly found in patients with PAH, such as endothelin or PDGF, flip an “on” switch that up-regulates a transcription factor called STAT-3. It up-regulates PIM-1, which in turn, activates another transcription factor called NFAT.

In 2007, Bonnet’s team showed that NFAT plays an important role in suppressing apoptosis (programmed cell death) and increasing the proliferation of smooth muscle cells in pulmonary arterial walls.

“As soon as NFAT is activated by PIM-1, the remodeling process starts in the pulmonary arteries,” explains Bonnet. This remodeling increases arterial resistance, eventually leading to narrowed arteries and life-threatening arterial blockages.

Latest findings implicate miRNAs

 The team’s most recent discovery may explain why drugs that block endothelin receptor and other vasoactive agents in the blood of patients with PAH don’t work as effectively as researchers had hoped.

They have discovered that the same switch that activates the STAT-3/PIM-1/NFAT cycle turns on other miRNAs within the cell. These miRNAs build a positive feedback loop that sustains the STAT-3/PIM-1/NFAT cycle independently – without need of further stimulation from growth factors or vasoactive agents.

“Once the switch is on, you can’t turn it off, because of the miRNAs,” Bonnet explains.

A new drug target

Neither STAT-3, which plays a role in angiogenesis and other normal physiologic responses, nor NFAT, which is involved in normal immune responses, are good therapeutic targets.

Bonnet believes that blocking PIM-1, on the other hand, can stop NFAT activation in diseased pulmonary arteries with little or no consequence to normal cells.

“The good thing is that PIM-1 is not expressed in healthy cells,” he says. “It is not implicated in important physiological processes. So, if we develop a drug to block PIM-1, it should only affect the sick cells and not have any bad effects on the healthy ones.”

Drugs that inhibit PIM-1 and prevent NFAT activation may restore apoptosis, halt the proliferation of abnormal smooth muscle cells in the walls of pulmonary arteries, and put an end to the remodeling process in patients with PAH. 

In experimental models, blocking the expression of PIM-1 has reversed the development of PAH with no measurable adverse effects.

Bonnet and his team, in partnership with the pharmaceutical industry, are currently testing a batch of newly developed PIM-1 inhibitors to measure their effectiveness and toxicity in experimental models. If these preliminary tests show promising results, Bonnet hopes that early-phase clinical trials with PIM-1 inhibitors can start within 2 years.

Dr. Bonnet’s work is funded by the Heart & Stroke Foundation of Canada, Canadian Research Chair program, and Canadian Institutes of Health Research.

 

 

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