Grant: Project Grant

Patients with pulmonary arterial hypertension have a dysfunction of the cells constituting the wall of their arteries in the lungs. Like cancer cells, PAH cells are characterized by exaggerated capacity to multiply and resistance to death resulting in a progressive narrowing or obstruction of the vessels. Indeed, if the blood vessels tighten up, making the space for the passage of blood narrower, it takes greater pressure to get the same amount of blood through to its destination. The heart has to work harder to pump blood through those arteries. The heart progressively fails causing shortness of breath and poor exercise capacity, which rapidly culminate in death. In spite of recent progress in our understanding of the mechanisms involved in this disease, no substantial modification of the rapid progression and fatal course of this disease has been achieved, leaving lung transplantation as the only treatment in end-stage PAH. Therefore, the identification of new therapeutic targets is a pressing need. In the present proposal, we hypothesize that a factor called ACLY, known to be responsible for the acquisition of the abnormal properties of cancer cells and overexpressed in PAH cells, contributes to the obstruction of the vessels in PAH. To test the validity of our hypothesis, we will 1) determine whether ACLY contributes to PAH cells' anomalies; 2) decorticate the mechanisms by which ACLY acts; and 3) assess whether inhibition of ACLY improves PAH in animal models.