VMI investigators Elena Goncharova, PhD, and Stephen Chan, MD, PhD study how pulmonary hypertension develops in order to design better therapeutic interventions to prevent, regress, or cure this devastating cardiopulmonary disease. During the past year, both investigators have made remarkable discoveries in the molecular pathways that cause remodeling of pulmonary vascular tissue and limit blood flow between the heart and lungs. These discoveries will help identify drug targets that are likely to stop or significantly slow the disease progression.
Dr. Goncharova and her laboratory discovered a new mechanism that drives pathogenic proliferation and impairs apoptosis of vascular smooth muscle cells in small pulmonary arteries. They found that HIPPO, a key growth suppressor cassette that prevents organ overgrowth, is dysfunctional in small pulmonary arteries of patients with pulmonary arterial hypertension. This results in activation of transcriptional co-activators YAP and TAZ, unleash other pro-proliferative pro-survival signaling pathways and increases cell proliferation and survival. The researchers identified ILK1 as a key molecule that “locks” HIPPO in inactive state and showed that pharmacological inhibition of ILK1 restores HIPPO function and stops the cyclical process of molecular activations that causes dangerous cell proliferation and apoptosis resistance in pulmonary hypertension patients’ arteries. Selective ILK inhibitors can now be further explored as a promising strategy for therapeutic intervention to reverse pulmonary hypertension.
Dr. Chan and his laboratory discovered a novel link between pulmonary vessel wall stiffening and the way that these blood vessels create energy and biomass. Dr. Chan’s group found that this link is primarily controlled by the activation of YAP and TAZ which in turn control an enzyme called glutaminase. Activation of glutaminase sets in motion a metabolic process that ends in dangerous cell proliferation in the arteries of pulmonary hypertension patients. The Chan lab identified the YAP inhibitor verteporfin and the glutaminase inhibitor CB-839 as therapeutic drug candidates when used, either singly or together, can impede the molecular pathways driving this deadly disease.