Grant: Project Grant

Patients with pulmonary hypertension (PHT; high blood pressure in the lungs) have a dysfunction of the cells constituting the wall of their arteries in the lungs. These cells proliferate like cancer cells and create an obstruction of the vessels, making it difficult for the blood to go through. Their right chamber of the heart fails as it has to pump against increased pressure, causing many symptoms like shortness of breath, poor exercise capacity, and eventually death. They also have evidence of inflammation in their blood, similar to patients suffering from infections. Although we know that this inflammation is detrimental to the blood vessels and the heart, we do not know its cause in PHT. Finally, evidence of insulin resistance has been found in patients with PHT like in diabetic patients, and again without known cause. All these organs have something in common: they display the same abnormal way to produce energy (metabolism). We therefore hypothesized that factors circulating in the whole body could be responsible for this overall aberrant metabolism seen in organs otherwise unconnected. We were particularly interested in Prohibitin (PHB), a circulating factor that has been found increased in the serum of patients with cancer, another disease with multi-organ metabolism abnormalities. We propose to study the role of circulating PHB in PHT. We will determine 1) whether PHB levels are increased in the blood of humans and animal models of PHT; 2) the potential of PHB to change arterial cells' metabolism, proliferation and survival, and to induce PHT in animals; 4) the mechanisms by which circulating PHB acts; 5) whether the inhibition of these mechanisms improve PHT in human cells and animals. If this is proven to be true in humans, it will have a tremendous impact on our knowledge regarding how PHT starts and progresses and may reveal new ways to treat the disease.